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Frontiers in Chemical Biology ·

Volume 5 - 2026 | https://doi.org/10.3389/fchbi.2026.1746130

Antibacterial potential of mono- Ru(II) and bi-metallic Ru(II)-Mn(II) inorganic compounds with phosphino-fluoroquinolone conjugates

  • Daria Wojtala1
  • Sandra Kozieł1*corresponding author
  • Jakub Łoś1
  • Katarzyna Guz-Regner2
  • Monika K. Lesiów1
  • Magdalena Szmitka1
  • Kacper Kardas1
  • Malwin Bajkowski1
  • Gabriela Bugla-Płoskońska2
  • Urszula K. Komarnicka1,3*corresponding author
  1. 1Faculty of Chemistry University of Wrocław, Wrocław, Poland
  2. 2Department of Microbiology, Faculty of Biological Sciences University of Wroclaw, Wroclaw, Poland
  3. 3Department of Chemistry, Colorado State University, Fort Collins, CO, United States
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Abstract

Herein, we present two novel heterobimetallic complexes Ru(II)-Mn(II) (Ru(η 6 - p -cymene)Cl 2 PCpMnCl 2 (H 2 O) 2 (RuPCpMn) and Ru(η 6 - p -cymene)Cl 2 PNrMnCl 2 (H 2 O) 2 (RuPNrMn)) with phosphines (PCp, PNr) derived from fluoroquinolones antibiotics (HCp–ciprofloxacin and HNr–norfloxacin). Compounds were characterized using elemental analysis, Fourier-transform infrared spectroscopy (FT-IR), electron paramagnetic resonance (EPR), electronic absorption spectroscopy (UV-Vis), and electrospray ionization mass spectrometry (ESI-MS). The antibacterial activity in vitro of heterobimetallic complexes together with literature monometallic Cu I and Ru II complexes possessing the same and different phosphine ligands was evaluated. The results indicate that structural modifications of metal-fluoroquinolone complexes affect their antibacterial properties. The mononuclear ruthenium(II) complexes exhibited broad-spectrum activity, particularly against Gram-negative bacteria, whereas the incorporation of manganese(II) ions did not lead to substantial improvement of antibacterial activity in vitro. However, complexes containing phosphine ligands without fluoroquinolone motifs but with, e.g., alkaloid, exhibited significantly reduced activity, emphasizing the importance of maintaining the pharmacophoric integrity of the fluoroquinolone core.

Keywords

1 Introduction

Antimicrobial resistance (AMR) is one of the most critical global health problems and is progressively considered as a silent pandemic. Currently, it is among the top ten threats to global public health (Ahmed et al., 2024). It was also reported that nearly five million deaths in 2019 were related to AMR. According to the World Health Organization (WHO), if antimicrobial resistance is not brought under control, it will lead to catastrophic consequences, with projections of up to 92 million deaths and an economic burden exceeding $100 trillion by 2050 (Guevara et al., 2023). To address these challenges, there is an urgent need to develop antimicrobial drugs that act through multi-target mechanisms, thereby reducing the chance of resistance development.

Over the past few decades, quinolone antibiotics have been developed from a relatively small group of drugs, used primarily to treat urinary tract infections, into one of the most frequently prescribed class of antibiotics worldwide. Currently, these compounds are used to treat a wide range of infections caused by both Gram-negative and Gram-positive bacteria. However, the clinical utility of quinolones is gradually limited by the emergence of resistance. The increasing resistance threatens the long-term efficacy of quinolones and highlights the urgent need to develop strategies to preserve their therapeutic value and develop new drug modifications that overcome these limitations (Aldred et al., 2014; Anacona and Toledo, 2001).

For this reason, metal-based antimicrobials turned out to be promising candidates (Wang C. et al., 2025). Traditionally metallodrugs were used for therapeutic purposes before the arrival of organic antibiotics. Early examples include Salvarsan, introduced for syphilis treatment, and its derivative Neosalvarsan (Bosch and Rosich, 2008). Bismuth preparations such as Bismuth subsalicylate (Hailey and Newsom, 1984) and Colloidal Bismuth Subcitrate have long been used in gastrointestinal infections (Lee, 1991). In topical therapy, Silver Sulfadiazine remains a standard for burn wound infections (Fox and Modak, 1974), while Auranofin has recently attracted attention for repurposing against multidrug-resistant bacteria (Thangamani et al., 2016). Undeniably, metallodrugs are now attracting renewed interest due to their unique structural and physicochemical properties. They exhibit diverse coordination geometries and can interact with biological targets through variety of mechanisms, including covalent binding to biomolecules, redox activity, and photochemical or radiochemical processes (Smitten et al., 2020; Frei, et al., 2020; Komarnicka et al., 2018; Boros et al., 2020; Wojtala et al., 2023; Kozieł et al., 2025a; Kozieł et al., 2025b). Furthermore, several metal-based drugs are already in clinical use in the treatment of non-infectious diseases, confirming their therapeutic potential and safety profile (Boros et al., 2020). These characteristics make metallo-antibacterials a viable alternative or adjuvant to traditional antibiotics, offering a multifaceted approach to combating multidrug-resistant pathogens.

In this context, we are presenting the antibacterial potential of literature RuII organometallic compounds (Ru(η6-p-cymene)Cl2PCp (RuPCp) and Ru(η6-p-cymene)Cl2PNr (RuPNr)) (Kołoczek et al., 2018) and new heterobimetallic compounds RuII-MnII (Ru(η6-p-cymene)Cl2PCpMnCl2(H2O)2 (RuPCpMn) and Ru(η6-p-cymene)Cl2PNrMnCl2(H2O)2 (RuPNrMn)) with phosphines (PCp, PNr) derived from fluoroquinolone antibiotics (FQ; HCp–ciprofloxacin and HNr–norfloxacin).

We have selected ruthenium(II) and manganese(II) ions to synthesize novel coordination compounds possessing fluoroquinolone motifs. A recent large-scale screening study evaluating around 1000 metal-containing compounds for antimicrobial activity revealed that ruthenium is the most abundant element among the active compounds with low toxicity to eukaryotic cells, followed by silver, palladium, and iridium (Frei et al., 2020; Munteanu and Uivarosi, 2021). Moreover, various scientific reports have presented that RuII coordination compounds, mostly with N-donor ligands, such as 2,6-bis(1,2,3-triazol-4-yl)pyridine (O’Reilly et al., 2021), phenylsulfonyl indole derivatives (Lin et al., 2025), as well as 2,2′-bipyridine and naphthalene derivatives (Liu et al., 2022), exhibit not only antibacterial activity in vitro or in vivo towards, e.g., Staphylococcus aureus, but also reduce bacterial pathogenicity by inhibiting biofilm formation. Significantly, this would prevent the generation of bacterial resistance (O’Reilly et al., 2021; Wang et al., 2022; Lin et al., 2025). These findings highlight the remarkable potential of ruthenium-based complexes as promising candidates for antimicrobial drugs development (Li F. et al., 2015; Frei et al., 2020). Manganese(Mn) is an essential trace element present in all tissues and biological fluids and is a key component of numerous metalloenzymes involved in fundamental physiological processes (Martins et al., 2025). It plays a diverse role in human health, including regulating immune responses, maintaining blood glucose homeostasis, cellular energy metabolism, bone development, cholesterol synthesis, and blood coagulation. Furthermore, manganese contributes significantly to antioxidant defense by participating in the detoxification of reactive oxygen species (ROS) via enzymes such as manganese superoxide dismutase (Avila et al., 2013; Kozieł et al., 2024; Martins et al., 2025). Due to these important functions, manganese-based materials are becoming increasingly popular in biomedical research (Bilyachenko et al., 2023; El-Zahed et al., 2024; Gandra et al., 2024; Vechalapu et al., 2024; Abbass et al., 2025; Ahmad and Choudhary, 2025; Czylkowska et al., 2025; El-bendary et al., 2025; Wang L.-H. et al., 2025; Woźnicka et al., 2026; Kalaiselvan et al., 2022; Zheng et al., 2022; Kumar Singh et al., 2023; Kozieł et al., 2024). Recent studies have been exploring manganese-containing nanomaterials and coordination compounds for their potential applications in anticancer (Vechalapu et al., 2024; Abbass et al., 2025; Czylkowska et al., 2025; El-bendary et al., 2025; Wang L.-H. et al., 2025; Woźnicka et al., 2026), antibacterial (Ahmad and Choudhary, 2025), and antifungal therapies (Bilyachenko et al., 2023; El-Zahed et al., 2024; Gandra et al., 2024), exploiting their redox activity (Bilyachenko et al., 2023; El-Zahed et al., 2024; Vechalapu et al., 2024) and biocompatibility to develop novel therapeutic strategies.

Considering above-mentioned evidence, this work focuses on examining the structural features and biological properties of ruthenium-manganese-containing compounds and comparing them with related systems to better understand how coordination chemistry influences antimicrobial efficacy.

2 Results and discussion

2.1 Synthesis and characterization

The new two heterobimetallic complexes RuII-MnII were synthesized (Scheme 1) by stirring at room temperature MnCl2 x 4H2O with 1 equiv. of mononuclear Ru(II) complexes with phosphine derivatives of fluoroquinolones ([Ru(η6-p-cymene)Cl2PCp (RuPCp; HCp - ciprofloxacin), Ru(η6-p-cymene)Cl2PNr (RuPNr; HNr - norfloxacin) reported by us in a previous study (Kołoczek et al., 2018).

Schematic procedures of new heterodinuclear Ru<sup>II</sup>-Mn<sup>II</sup> coordination compounds synthesis.
Figure 1. Schematic procedures of new heterodinuclear RuII-MnII coordination compounds synthesis.

Heteronuclear complexes are soluble in CH3OH, DMSO and CH2Cl2 and poorly soluble in water, whereas they can be solubilized in water containing 2% of DMSO. All the synthesized coordination compounds were fully characterized in solid state by CHN elemental analysis and Fourier transform infrared spectroscopy (FT-IR) (Figures 1a,b) and in solution by electron paramagnetic resonance (EPR) (Figures 1c,d), electronic absorption spectroscopy (Supplementary Figures S1, S2) and electrospray ionization mass spectrometry in positive ion modality (ESI(+)MS) (Supplementary Figures S3–S12). Additional stability studies were performed in an aqueous media solution using absorption spectroscopy (Supplementary Figures S1, S2). Below, we present a shortened discussion on the structures of new heterodinuclear compounds (Sadeek, 2005; Ogino et al., 2009; Batista et al., 2011; Sadeek, 2005; Ogino et al., 2009; Batista et al., 2011). The FT-IR spectra of RuPCp, RuPCpMn, RuPNr, and RuPNrMn are shown in Figure 1 (detailed discussion in ESI). The manganese-containing complexes exhibit broad bands in the range 3,498–3,410 cm−1, indicating coordinated water. Mononuclear RuPCp and RuPNr exhibit carboxylate v(COOH) bands in the range 1720 cm−1, which disappear upon complexation with Mn2+, confirming carboxylate coordination. In the crowded region 1630–1350 cm-1, the bands in the range 1625–1630 cm−1 in RuPCpMn and RuPNrMn correspond to asymmetric carboxylate stretching. The parent antibiotics show v(CO) at ∼1630 cm−1, while in the Mn complexes it shifts to a shoulder around 1615 cm−1 due to interaction with metals, which is consistent with the results for other quinolone complexes. The spectra also show characteristic Mn–O vibrations at ∼630 and 540 cm-1, which is consistent with literature data (Sadeek, 2005; Ogino et al., 2009; Batista et al., 2011).

The FT-IR spectra of **(a)** RuPCp and RuPCpMn, **(b)** RuPNr and RuPNrMn complexes in the 4,000-100 cm<sup>-1</sup> region; **(c)** Experimental (exp) and simulated (sim) EPR spectra for frozen (77 K) solutions of RuPCpMn complex in DMSO; **(d)** Experimental (exp) and simulated (sim) EPR spectra for frozen (77 K) solutions of RuPNrMn complex in DMSO. All simulations of EPR spectra were carried out using Doubletexact (SPIN = ½: EXACT) program implemented by Andrew Ozarowski.
Figure 2. The FT-IR spectra of (a) RuPCp and RuPCpMn, (b) RuPNr and RuPNrMn complexes in the 4,000-100 cm-1 region; (c) Experimental (exp) and simulated (sim) EPR spectra for frozen (77 K) solutions of RuPCpMn complex in DMSO; (d) Experimental (exp) and simulated (sim) EPR spectra for frozen (77 K) solutions of RuPNrMn complex in DMSO. All simulations of EPR spectra were carried out using Doubletexact (SPIN = ½: EXACT) program implemented by Andrew Ozarowski.

Romanowski et al. (2010), Šimėnas et al. (2016) the EPR spectra of RuPCpMn and RuPNrMn show isotropic signals with the characteristic six-line hyperfine pattern of Mn2+ (I = 5/2) (Figure 1b). Simulation of the spectra gives g_iso = 2.003 and A_iso = 92G for RuPCpMn and g_iso = 2.003 and A_iso = 90G for RuPNrMn. These values are typical for octahedral Mn2+ complexes. The parameters closely match literature data for related Mn2+ systems (g_iso ≈2.006–2.008; A_iso ≈91–94G), confirming the assignment and suggesting a similar octahedral coordination environment (Romanowski et al., 2010; Šimėnas et al., 2016).

All complexes were examined by ESI-MS in positive mode (Supplementary Figures S3–S12). Protonated or sodiated RuPCpMn and RuPNrMn species were clearly detected, along with fragment ions such as [M–Cl]+ and [M – 2Cl + H2O+ Na]+, indicating the easy loss of chloride ions during ionization. Solvent adducts (H2O, CH3OH) also appeared, indicating that these species can replace the chloride ion in the coordination sphere. Further fragmentation produced ions resulting from the loss of Ru(η6-p-cymene)Cl2 and phosphine ligands, confirming the relatively weak Ru–ligand interaction. In contrast, Mn2+ remained more strongly bound to the fluoroquinolone ligands. The experimental isotope patterns matched the simulated spectra (Supplementary Figures S3–S12), confirming the proposed compositions and fragmentation pathways.

The UV–Vis spectroscopy (Supplementary Figures S1, S2) was used to evaluate the structural stability of the investigated RuPNrMn and RuPCpMn complexes in methanol (Supplementary Figures S1A, S2A) and in aqueous solutions. Additional stability studies were performed in a water/DMSO mixture (80%:20% v/v) (Supplementary Figures S1B, S2B) and in Dulbecco’s Modified Eagle’s Medium (DMEM) cell culture medium (Supplementary Figures S1C, S2C), because preservation of complex integrity under biologically relevant conditions is crucial for subsequent cellular studies. Each complex shows three bands in the UV region assigned based on their electronic structure. The intense band observed at ca. 210 nm is attributed to ligand-centered π→π* transitions of the aromatic moieties. The absorption maximum at around 280 nm arises from lower-energy intraligand π→π* transitions, with a possible minor contribution from n→π* transitions associated with heteroatom-containing groups (de la Luz Pérez-Arredondo et al., 2015; Tamer, 2017; Kozieł et al., 2020). The band appearing at ca. 330 nm is characteristic for a metal-to-ligand charge-transfer (MLCT) transition, corresponding to electron transfer from RuII d orbitals to the π* orbitals of the coordinated ligand, which is typical for RuII complexes (Kumar et al., 2018; Klaimanee et al., 2021; Deng et al., 2023; Kozieł et al., 2025a).

In aqueous media and in the water/DMSO mixture, only a slight decrease in maximum of absorbance (approximately 15%) was observed over 48 h, indicating moderate dissociation of chlorido ligands from the RuII–MnII complexes and the formation of aqua species. In contrast, a more pronounced decrease in absorbance was detected in DMEM; however, it did not exceed 30% over the same period. This enhanced spectral change can be attributed to the increased chemical complexity of the DMEM medium, which contains various inorganic salts, amino acids, vitamins, and glucose (Lyra-Leite et al., 2023; Cao et al., 2020; Cao et al., 2025; Xiao and Högger, 2015) that may promote ligand exchange processes, weak coordination interactions, or partial substitution of chloride ligands (Kozieł et al., 2020; Kozieł et al., 2025a; Komarnicka et al., 2022; Zhang et al., 2022; Wojtala et al., 2023). In particular, it has been reported that metal complexes may undergo partial degradation in the presence of sulfur-containing biomolecules, such as thiol-bearing amino acids and peptides (Lenz and Martell, 1964; Hartinger et al., 2008; Tanifuji et al., 2023; Wojtala et al., 2023; Khadivi-Derakhshan et al., 2025). For example, our previous studies demonstrated the formation of bio-adducts between IrIII complex and glutathione (GSH) or ascorbate, Whereas in the RuII coordination compound, the excess of GSH induced loss of one of the chlorido ligands (Wojtala et al., 2023). On the other hand, several research groups reported that half-sandwich RuII compounds could form adducts with glutathione, that mostly consists of metal center and biomolecule (Hartinger et al., 2008; Briš et al., 2019; Gilewska et al., 2019). For instance, Casini and co-workers reported the formation of multiple thiolate species of RAPTA-C in the presence of excess GSH (Hartinger et al., 2008). Such interactions may also lead to partial ligand dissociation, including phosphine release. However, these processes are not directly observable in the presented UV–Vis spectra due to the strong overlap of ligand-centered absorption bands (Wojtala et al., 2023). Importantly, despite these potential interactions, the overall spectral profiles indicate that the investigated complexes retain sufficient stability under biologically relevant conditions, consistent with the behavior previously reported for similar complexes (Li et al., 2019; Komarnicka et al., 2022; Liu et al., 2023; Komarnicka, et al., 2022; Wojtala et al., 2023; Kozieł et al., 2025a).

3 Antibacterial activity in vitro

In this study, we evaluated the antibacterial activity of ruthenium-based complexes with or without manganese(II) ion: RuPCp, RuPCpMn, RuPNr, and RuPNrMn showing low toxicity toward normal cells (preliminary data shown in Supplementary Figure S13 for HEK293T and HaCaT cell lines). Although the primary focus was on determining their biological properties, we also conducted a comparative analysis with compounds (Figure 2) reported in the literature that share similar phosphine ligands but differ either in the central metal ion (CuI: CuPCp: CuI(dmp)PCp; CuPNr: CuI(dmp)PCp) (Guz-Regner et al., 2020) or in the nature of the coordinated ligands (RuPNMPEA: Ru(η6-p-cymene)Cl2PNMPEA, PNMPEA: Ph2PCH2N(CH3) (CH2)2Ph) (Wojtala et al., 2023) together with parent drugs (HCp, HNr) (Guz-Regner et al., 2020), phosphines derived from these antibiotics (PCp, PNr) (Guz-Regner et al., 2020) and starting RuII dimer (Wojtala et al., 2023). This approach allowed us to investigate how variations in coordination environment, metal identity, and ligand architecture affect antibacterial efficacy. Such a comparative assessment provides valuable information on the structure-activity relationships (SARs) of metal-fluoroquinolone complexes and highlights the role of steric and electronic factors in modulating biological efficacy.

Schematic structures of fluoroquinolone antibiotics (HCp–norfloxacin, HCp–ciprofloxacin); phosphines (PCp, PNr); Ru<sup>II</sup> (RuPNMPEA) and Cu<sup>I</sup> complexes (CuPCp, CuPNr), which antibacterial activity *in vitro* have been compared to the RuPCpMn and RuPNrMn one.
Figure 3. Schematic structures of fluoroquinolone antibiotics (HCp–norfloxacin, HCp–ciprofloxacin); phosphines (PCp, PNr); RuII (RuPNMPEA) and CuI complexes (CuPCp, CuPNr), which antibacterial activity in vitro have been compared to the RuPCpMn and RuPNrMn one.

The antibacterial activity in vitro of the synthesized compounds demonstrates a clear relationship between structural features and biological efficacy. Their minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs) against Gram-positive and Gram-negative bacteria exhibit distinct trends that emphasize the influence of metal coordination and ligand architecture on antimicrobial potential (Table 1; Supplementary Table S1). Free fluoroquinolone ligands (HCp, HNr) exhibit the highest activity against Klebsiella pneumoniae, with MICs as low as 0.004–0.030 μg/mL. This exceptional potency is consistent with the well-established mechanism of action of fluoroquinolones, which involves inhibition of bacterial DNA gyrase and topoisomerase IV (Aldred et al., 2014). Phosphines derived from fluoroquinolones (PCp, PNr) retain similar activity profiles, confirming that the fluoroquinolone core remains the dominant pharmacophore. Coordination with ruthenium(II) ion alters the antibacterial profile. Coordination compounds containing Ru(η6-p-cymene) moiety (RuPCp and RuPNr) exhibit broad-spectrum activity, particularly against E. coli and K. pneumoniae, with MIC values ​​ranging from 0.0625 to 2.0000 μg/mL. The slight decrease in the antibacterial activity in vitro, after the coordination of phosphine-fluoroquinolone conjugate to the RuII ion, may result from the insufficient ability to cross the outer-membrane of Gram-negative bacteria or biofilm in both Gram-negative and Gram-positive bacteria, due to the higher established octanol-water partition coefficient (log P) values (HCp: −0.57, RuPCp: 6.28, HNr: −0.47, RuPNr: 6.29) (calculated using program ALOGPS 2.1 (Petrauskas and Kolovanov, 2000; Molinspiration, 2026; Zhao et al., 2020; Ruhal and Kataria, 2021); Whereas the incorporation of more lipophilic phosphine ligands, e.g., with N-methylphenethylamine moiety (RuPNMPEA, logP = 7.56), significantly reduces activity (MIC from 8.0 to >16 μg/mL) (Wojtala et al., 2023).

TABLE 1. MIC [µg/mL] (the minimum bacterial inhibitory concentration) values for HCp, HNr, PCp, PNr, RuPCp, RuPNr, RuPNMPEA, CuPNr, CuPCp, RuPNrMn, RuPCpMn and RuII dimer.

Bacterial strainsCuPNr aCuPCp aRuPNMPEA bRu dimer bHCp aPCp aHNr aPNr aRuPCpRuPCpMnRuPNrRuPNrMn
Gram-negative
Escherichia coli ATCC 11922--------0.50002.02.01.0
Klebsiella pneumoniae ATCC 43521.00.2500--0.00400.00400.03000.030.06250.25000.25000.2500
Pseudomonas aeruginosa ATCC 27853>16.016.0>16.0>16.00.12500.12500.50001.02.04.04.04.0
Yersinia enterocolitica c--------1.02.02.02.0
Gram-positive
Enterococcus faecalis ATCC 29212-->16.0>16.0----2.016.04.08.0
Bacillus subtilis ATCC 6633--16.0>16.0----1.04.02.02.0
Staphylococcus aureus ATCC 6538>16.02.08.0>16.00.12500.12500.50001.02.08.02.02.0
Micrococcus luteus ATCC 4698--16.0>16.0----4.08.04.0>16.0

Guz-Regner et al. (2020).

Wojtala et al. (2023).

Collection of Department of Microbiology, Faculty of Biological Sciences University of Wroclaw, Poland.

The MBC values for fluoroquinolone (FQ)–phosphine derivatives in complexes with RuII ions and RuII/MnII ions were highly variable and generally equal to the MIC or 2×MIC for Gram-negative bacteria and between the MIC and 4×MIC for Gram-positive bacteria. The lowest susceptibility was observed for M. luteus and E. faecalis, for which the MBC values ranged from 2×MIC to 4×MIC. Incorporating manganese(II) into ruthenium(II) complexes (RuPCpMn and RuPNrMn) does not enhance antimicrobial potential (except a modest improvement for NPr complexes). Although MnII ions may contribute to oxidative stress in bacterial cells (Si et al., 2017; Bosma et al., 2021; Martin and Waters, 2022), the increased steric bulk and altered coordination environment appear to offset these potential benefits, resulting in MIC values that are generally higher than those of monometallic RuII complexes (Table 1; Supplementary Table S1). Nevertheless, these compounds demonstrated a consistent bactericidal effect across all tested bacterial strains, as evidenced by MBC/MIC ratios ranging from 1 to 2, which is indicative of bactericidal activity (Table 1; Supplementary Tables S1, S2).

Similarly, copper-based complexes (CuPCp and CuPNr, Figure 2) exhibit selective activity, demonstrating strong inhibition of K. pneumoniae growth (MIC = 0.25–1.00 μg/mL) but negligible effects on other strains. This suggests that copper(I) ions may induce oxidative damage or disrupt enzymatic processes in specific bacterial species, but its overall spectrum of activity remains limited. Interestingly, coordination of manganese(II) ions various fluoroquinolone drugs, such as ciprofloxacin, lomefloxacin or pipemidic acid, maintained antibacterial activity in vitro as it was demonstrated via the disc diffusion or the microtiter broth dilution methods in several papers (El-Halim et al., 2011; Uivarosi, 2013). This phenomenon can be explained by many reasons like bacterial resistance to metal ions (Uivarosi, 2013; Chandrangsu et al., 2017; Balta et al., 2025) or decomposition of fluoroquinolone moiety by manganese(II) ions leading to significant inhibition of antibacterial activity of discussed compounds in this paper (Uivarosi, 2013; Almeida Lage et al., 2018).

Comparison of Gram-staining trends reveals that Gram-negative bacteria, particularly K. pneumoniae and E. coli, are more sensitive to both free ligands (HCp, HNr) and ruthenium(II) complexes (RuPCp, RuPNr) than Gram-positive strains such as Staphylococcus aureus or Bacillus subtilis. This difference likely reflects differentiations in cell wall architecture and permeability, as well as the presence of efflux mechanisms in Gram-positive organisms. The collected data indicate that structural modifications, including metal coordination and ligand substitution, have a profound impact on antibacterial activity. Ruthenium complexes appear promising candidates for broad-spectrum applications, while phosphino-fluoroquinolone derivatives retain exceptional efficacy against specific Gram-negative pathogens. Taken together, these findings underscore the importance of rational design in the development of metal-based antimicrobial drugs. The balance between pharmacophoric ligand integrity, metal coordination, and spatial accessibility determines biological efficacy.

4 Conclusion

The present study demonstrates that structural modification of fluoroquinolones (FQs) to Ru-based coordination complexes alters but generally does not enhance antibacterial activity compared to the parent ligands. Although RuII FQ–phosphine complexes (RuPCp, RuPNr) exhibit a broad spectrum of activity, their potency is lower than that of the corresponding free FQs. Thus, it would be erroneous to conclude that RuII coordination improves antimicrobial efficacy compared to the free ligands; any observed activity likely reflects intrinsic Ru-related effects combined with, but not surpassing, the pharmacology of the FQ core. Incorporating MnII to form heterobimetallic species (RuPCpMn, RuPNrMn) did not improve potency and, in most cases, increased MIC values ​​compared to monometallic RuII analogues, consistent with additional steric/electrostatic constraints in the coordination domain that may hinder productive interactions with bacterial targets or transport. Cu-based analogues also exhibited narrower activity (e.g., selective activity against K. pneumoniae) without achieving broad spectrum activity.

Comparison of our series and literature precedents highlights that metal identity and ligand architecture (especially retention of the fluoroquinolone pharmacophore) are crucial for biological outcomes. Complexes that dilute or mask the FQ pharmacophore, e.g., those built around bulky phosphines without FQ motifs, typically exhibit significantly reduced activity, emphasizing the need to maintain pharmacophoric integrity when designing metal-antibiotic hybrids.

Overall, although ruthenium-FQ complexes remain of interest like chemical probes and scaffolds for mechanistic studies (e.g., transport, redox reactions, or multi-target engagement), the current results do not support a general efficacy advantage over the parent FQ. Therefore, future work should (i) prioritize SAR that preserves the FQ pharmacophore and minimizes steric burden, (ii) distinguish metal-center effects from ligand-dependent activity (e.g., by including metal-only and ligand-only controls and orthogonal capture assays), and (iii) explore synergistic designs (e.g., Ru complexes as adjuvants), rather than assuming that coordination per se will enhance antibacterial activity. This strategy will provide a clearer path to rational design and a more realistic assessment of therapeutic potential.

5 Experimental section

5.1 General procedures

All starting reagents including a 2nd generation fluoroquinolone (HCp, HNr) (>98%), Ru(η6-p-cymene)Cl2]2 (>98%), MnCl2 and solvents were purchased from Sigma-Aldrich and used without further purifications. All solvents were deaerated prior to use. Mononuclear complexes (RuPNr and RuPCp) (Kołoczek et al., 2018) and aminomethyl(diphenyl)phosphines (PNr and PCp) (Bykowska et al., 2014) were synthesized as described previously.

5.2 Characterization of heteronuclear ruthenium(II)-manganese(II) complexes

Elemental analyses (C, H and N) were carried out with a Vario Micro Cube–Elementar. Mass spectra were recorded with a Bruker MicrOTOF-Q II spectrometer with an ESI ion source under the following conditions: nebulizer pressure: 0.4 bar, dry gas flow: 4.0 Lmin-1 heated to 180 °C. Data were recorded in the positive ion mode, while profile spectra were recorded in the mass range 50–3,000 m/z; end plate offset −500 V; capillary voltage 4500 V; mass resolving power of the instrument–over 18 ,000. Mass calibration was done using the cluster method with a mixture of 10 mM sodium formate and isopropanol (1: 1, v/v) before the run. To record the spectra the compounds were dissolved in methanol. Electronic absorption spectroscopy was carried out with a UV-Vis spectrophotometer (Agilent Technologies, Cary300 UV-Vis). FT-IR spectra of complexes were recorded using a BrukerVertex 70 V vacuum spectrometer equipped with a diamond ATR cell with a resolution of 2 cm-1 in the middle-infrared (4,000-500 cm-1) and far-infrared (600-100 cm–1) regions at room temperature as solid-state and methanolic solutions (c = 0.80%) as well. The spectral data were collected and further elaborated using Bruker OPUS software. EPR experiments were performed using a Bruker Elexsys E500 spectrometer operating at 9.6 (X-band) frequency. The spectrometer was equipped with an NMR teslameter (ER 036TM) and a frequency counter (HP 5342 A). Spectra were recorded at 77 K for DMSO solutions (25 mg/mL). Microwave power was maintained in the range of 10–20 mW. All simulations of EPR spectra were carried out using Doubletexact (SPIN = ½: EXACT) program implemented by Andrew Ozarowski. The partition coefficients (logP) were calculated using the program ALOGPS 2.1 (Petrauskas and Kolovanov, 2000; Tetko and Tanchuk, 2002).

5.3 Synthesis

5.3.1 RuPCpMn (Ru(η6-p-cymene)Cl2PPh2CH2CpMnCl2(H2O)2)

The starting RuII complex, RuPCp ((Ru(η6-p-cymene)Cl2PPh2CH2Cp); 30.3 mg, 0.036 mmol), and MnCl2·4H2O (7.17 mg, 0.036 mmol) were dissolved in 30 cm3 of methanol. The mixture was stirred at room temperature for 24 h. During this time, the initially cloudy solution changed color from light orange to dark orange. After stirring, the mixture was filtered. The resulting filtrate was left to evaporate slowly at room temperature for another 24 h, leading to the precipitation of a dark orange crystalline precipitate. The compound is readily soluble in solvents such as chloroform, methanol, DMSO, and THF, but insoluble in water, n-hexane, toluene, and benzene.

Yield: 16.2 mg (45%), Molar mass: 996.60 g/mol.

Anal. Calcd for C40H47Cl4FN3O5PRuMn (RuPCpMnCl2·2H2O): C: 50.96%, H: 5.03%, N: 4.46%, Found: C: 50.82%, H: 5.16%, N: 4.34%,

ESI(+)MS in CH3OH, m/z: 437.2 (100%); 619.5 (34%); 836.2 (theor.: 836.1) (50%) [RuPCp]+; 493.4 (theor.: 493.1) (53%) [HCpMnCl2(H2O)2]Na+; 437.2 (theor.: 437.1) (21%) [HCpMn(H2O)3]+; 1019.9 (theor.: 1020.0) (7%) [RuPCpMn]Na+.

5.3.2 RuPNrMn (Ru(η6-p-cymene)Cl2PPh2CH2NrMnCl2(H2O)2)

A 1:1 M ratio of the starting materials was employed: RuPNr ((Ru(η6-p-cymene)Cl2PPh2CH2Cp); 38.2 mg, 0.046 mmol) and MnCl2·4H2O (9.17 mg, 0.046 mmol). Both reagents were quantitatively transferred and dissolved in 30 cm3 of methanol. The reaction mixture was stirred at ambient temperature for 24 h. Throughout this period, the solution retained its light orange coloration. Following the reaction, the mixture was filtered, and the resulting filtration was allowed to evaporate slowly at room temperature over an additional 24-h period. This process led to the formation of orange crystalline precipitates. The isolated compound exhibits good solubility in organic solvents such as chloroform, methanol, DMSO, and THF, while being insoluble in water, n-hexane, toluene, and benzene.

Yield: 16.8 mg (37%), Molar mass: 984.59 g/mol.

Anal. Calcd for C39H46Cl4FN3O5PRuMn (RuPNrMnCl2·2H2O): C: 50.33%, H: 5.09%, N: 4.52%, Found: C: 50.28%, H: 5.23%, N: 4.48%,

ESI(+)MS in CH3OH, m/z: 619.5 (theor.: 619.1) (100%) [PNrMn(H2O)2]H+; 966.7 (theor.: 967.0) (15%) [RuPNrMnCl2(H2O)]+; 847.3 (theor.: 847.1) (7%) [RuPNr]Na+; 607.6 (theor.: 607.1) (30%) [(PNr)2Mn(H2O)]+.

5.4 Antibacterial activity in vitro

The antibacterial activity of compounds was calculated by determining the MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) in the microtiter plate methods with a series of dilutions in broth (Guz-Regner et al., 2020). Bacteria Gram-negative (Escherichia coli ATCC 11922, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 27853, Yersinia enterocolitica wild strain) and Gram-positive (Enterococcus faecalis ATCC 29212, Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538, Micrococcus luteus ATCC 4698) inoculum (with final concentration 104 cfu/mL) in Luria Bertain broth (LB) supplemented with ≤1% DMSO was incubated with serial dilutions of tested compounds from 0.002 μg/mL to 32 μg/mL at the 25 °C (B. subtilis, Y. enterocolitica and M. luteus), as well as 35 °C (E. faecalis, E. coli, K. pneumoniae, P. aeruginosa and S. aureus) for 24 h. The MIC was determined as the lowest concentration compound inhibiting visible bacterial growth by spectrophotometric method. The OD (optical density) of each microtubes was measured at λ = 590 nm using automatic 96-wellmircoplate reader Asyss Hitachi 340, Driver Version: 4.02 (Biogenet). To determine the MBC of compound the agar dilution method was used. The bacterial inoculum treated with different concentrations of tested compounds were taken 10 μL aseptically from microtubes that had not presented visible turbidity and plated onto Muller-Hinton agar (MHA). Then the plates with spotted bacteria inocula were incubated at 25 °C or 35 °C for 24–48 h. The MBC was considered as the lowest concentration of compounds that allowed less than 0.1% of the original inoculum treated with tested compounds to grow on the surface of the agar MHA. To determine the nature of antibacterial effect of the tested compounds the MBC/MIC ratio is used (Wojtala et al., 2023). When this ratio is equal to or less than 4, the compound is considered as a bactericidal, and if this ratio is higher than 4, the compound is to be bacteriostatic. MIC and MBC determinations were performed in triplicate according to CLSL procedures (Guz-Regner et al., 2020; Wojtala et al., 2023).

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchbi.2026.1746130/full#supplementary-material

Supplementary material Supplementary material at the source

Footnotes

Edited by: Sylvia Mary Draper, Trinity College Dublin, Ireland

Reviewed by: Isabel Correia, University of Lisbon, Portugal

Joseph Byrne, University College Dublin, Ireland

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This research was funded by the National Science Centre, Poland (grant number 2023/51/B/ST4/00355 and 2023/49/N/ST4/00337) and Polish National Agency for Academic Exchange Stargetic Partnerships 2024 (grant number BPI/PST/2024/1/00028). UK is grateful to the Kosciuszko Foundation for funding her stay at Colorado State University.

Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Author contributions

DW: Investigation, Writing – review and editing, Funding acquisition, Supervision, Writing – original draft, Data curation. SK: Supervision, Conceptualization, Investigation, Writing – review and editing, Project administration, Writing – original draft, Formal Analysis, Visualization. JŁ: Data curation, Investigation, Writing – review and editing. KG-R: Supervision, Conceptualization, Writing – review and editing, Methodology, Formal Analysis. ML: Software, Writing – review and editing, Supervision, Formal Analysis. MS: Writing – review and editing, Writing – original draft. KK: Writing – review and editing, Writing – original draft. MB: Writing – review and editing, Writing – original draft. GB-P: Writing – review and editing. UK: Writing – review and editing, Methodology, Writing – original draft, Conceptualization, Funding acquisition, Supervision.

Acknowledgements

UK is grateful to Prof. Debbie C. Crans for insightful scientific discussions and for being a wonderful host during the visit at Colorado State University.

References

  1. Abbass L. M., Belaidi M., Bufarwa S. M., Sadeek S. A. (2025). Exploring the anti-colon cancer potential of febuxostat-based mixed metal complexes with 2,2′-bipyridine: MTT assay, toxicity evaluation, prediction profiles, and computational studies. Inorg. Chem. Commun. 178, 114460. doi:10.1016/j.inoche.2025.114460
  2. Ahmad R., Choudhary M. (2025). Synthesis and design of manganese and nickel complexes with potential anticancer and antibacterial activities and antiviral properties for therapeutic applications. New J. Chem. 49, 12401 – 12422. doi:10.1039/d5nj00268k
  3. Ahmed S. K., Hussein S., Qurbani K., Ibrahim R. H., Fareeq A., Mahmood K. A. (2024). Antimicrobial resistance: impacts, challenges, and future prospects. J. Med. Surg. Public Health 2, 100081. doi:10.1016/j.glmedi.2024.100081
  4. Aldred K. J., Kerns R. J., Osheroff N. (2014). Mechanism of quinolone action and resistance. Biochemistry 53, 1565 – 1574. doi:10.1021/bi5000564
  5. Almeida Lage A. L., Moreira Meireles A., Capelão Marciano A., Martins Ribeiro J., de Souza-Fagundes E. M., Carvalho da Silva Martins D. (2018). Ciprofloxacin degradation by first-second-and third-generation manganese porphyrins. J. Hazard. Mater. 360, 445 – 451. doi:10.1016/j.jhazmat.2018.08.036
  6. Anacona J. R., Toledo C. (2001). Synthesis and antibacterial activity of metal complexes of ciprofloxacin. Transit. Metal. Chem. 26, 228 – 231. doi:10.1023/A:1007154817081
  7. Avila D. S., Puntel R. L., Aschner M. (2013). Manganese in health and disease, 199 – 227. doi:10.1007/978-94-007-7500-8_7
  8. Balta I., Lemon J., Gadaj A., Cretescu I., Stef D., Pet I. (2025). The interplay between antimicrobial resistance, heavy metal pollution, and the role of microplastics. Front. Microbiol. 16, 1550587. doi:10.3389/fmicb.2025.1550587
  9. Batista D. da G. J., da Silva P. B., Stivanin L., Lachter D. R., Silva R. S., Felcman J. (2011). Co(II), Mn(II) and Cu(II) complexes of fluoroquinolones: synthesis, spectroscopical studies and biological evaluation against Trypanosoma cruzi. Polyhedron 30, 1718 – 1725. doi:10.1016/j.poly.2011.04.001
  10. Bilyachenko A. N., Gutsul E. I., Khrustalev V. N., Chusova O., Dorovatovskii P. V., Aliyeva V. A. (2023). A family of cagelike Mn-Silsesquioxane/Bathophenanthroline complexes: synthesis, structure, and catalytic and antifungal activity. Inorg. Chem. 62, 15537 – 15549. doi:10.1021/acs.inorgchem.3c02040
  11. Boros E., Dyson P. J., Gasser G. (2020). Classification of metal-based drugs according to their mechanisms of action. Chem 6, 41 – 60. doi:10.1016/j.chempr.2019.10.013
  12. Bosch F., Rosich L. (2008). The contributions of paul ehrlich to pharmacology: a tribute on the occasion of the centenary of his nobel prize. Pharmacology 82, 171 – 179. doi:10.1159/000149583
  13. Bosma E. F., Rau M. H., van Gijtenbeek L. A., Siedler S. (2021). Regulation and distinct physiological roles of manganese in bacteria. FEMS Microbiol. Rev. 45, fuab028. doi:10.1093/femsre/fuab028
  14. Briš A., Jašík J., Turel I., Roithová J. (2019). Anti-cancer organoruthenium(ii) complexes and their interactions with cysteine and its analogues. A mass-spectrometric study. Dalton Trans. 48, 2626 – 2634. doi:10.1039/C8DT04350G
  15. Bykowska A., Starosta R., Komarnicka U. K., Ciunik Z., Kyzioł A., Guz-Regner K. (2014). Phosphine derivatives of ciprofloxacin and norfloxacin, a new class of potential therapeutic agents. New J. Chem. 38, 1062. doi:10.1039/c3nj01243c
  16. Cao H., Yi L., Zhong J., Högger P., Wang M., Prieto M. A. (2020). Investigation of new products and reaction kinetics for myricetin in DMEM via an in situ UPLC–MS–MS analysis. Food Front. 1, 243 – 252. doi:10.1002/fft2.19
  17. Cao S., Zhang P., Song H., Ge L., Niu J. (2025). Photochemical properties and toxicity of fluoroquinolone antibiotics impacted by complexation with metal ions in different pH solutions. J. Environ. Sci. 150, 149 – 158. doi:10.1016/j.jes.2024.03.019
  18. Chandrangsu P., Rensing C., Helmann J. D. (2017). Metal homeostasis and resistance in bacteria. Nat. Rev. Microbiol. 15, 338 – 350. doi:10.1038/nrmicro.2017.15
  19. Czylkowska A., Lanka S., Rogalewicz B., Raducka A., Fornal E., Iwan M. (2025). Anticancer activity of the new manganese(II), iron(II), nickel(II), copper(II), and zinc(II) complexes based on 1,2,4-triazoline-3-thione derivative. J. Trace Elem. Med. Biol. 92, 127786. doi:10.1016/j.jtemb.2025.127786
  20. de la Luz Pérez-Arredondo M., del Refugio González-Ponce M., Ana Zanor G., Ramirez Vazquez J. A., Segoviano-Garfias J. J. N. (2015). Complex formation equilibria of 2,2′-bipyridyl and 1,10-phenanthroline with manganese(II) in methanol. Karbala Int. J. Mod. Sci. 1, 178 – 186. doi:10.1016/j.kijoms.2015.11.005
  21. Deng Y.-A., Tang S.-J., Wang M.-F., Ren X., Li X.-L., Zeng L.-Z. (2023). Heterometallic ruthenium–osmium complexes: dual photodynamic and photothermal therapy for melanoma and drug-resistant lung tumour in vivo. Inorg. Chem. Front. 10, 4552 – 4561. doi:10.1039/D3QI00903C
  22. El-bendary M. M., Akhdhar A., Domyati D., Ali E. M. M., Davaasuren B., Jaremko M. (2025). Structure characterization, DNA binding, molecular docking and antitumor activity of manganese isothiocyanate complex with neocuproine ligand. Polyhedron 267, 117364. doi:10.1016/j.poly.2024.117364
  23. El-Halim H. F. A., Mohamed G. G., El-Dessouky M. M. I., Mahmoud W. H. (2011). Ligational behaviour of lomefloxacin drug towards Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Th(IV) and UO2(VI) ions: synthesis, structural characterization and biological activity studies. Spectrochim. Acta A Mol. Biomol. Spectrosc. 82, 8 – 19. doi:10.1016/j.saa.2011.05.089
  24. El-Zahed M. M., Diab M. A., El-Sonbati A. Z., Nozha S. G., Issa H. R., El-Mogazy M. A. (2024). Antibacterial, antifungal, DNA interactions, and antioxidant evaluation of Cu(II) Co(II), Ni(II), Mn(II) and UO2(II) mixed ligand metal complexes: synthesis, characterization and molecular docking studies. Mater. Sci. Eng. B 299, 116998. doi:10.1016/j.mseb.2023.116998
  25. Fox C. L., Modak S. M. (1974). Mechanism of silver sulfadiazine action on burn wound infections.
  26. Frei A., Zuegg J., Elliott A. G., Baker M., Braese S., Brown C. (2020). Metal complexes as a promising source for new antibiotics. Chem. Sci. 11, 2627 – 2639. doi:10.1039/C9SC06460E
  27. Gandra R. M., Pacheco C. A., Sangenito L. S., Ramos L. S., Souza L. O. P., McCarron P. (2024). Manganese(II), copper(II) and silver(I) complexes containing 1,10-phenanthroline/1,10-phenanthroline-5,6-dione against Candida species. Future Microbiol. 19, 385 – 395. doi:10.2217/fmb-2023-0212
  28. Gilewska A., Barszcz B., Masternak J., Kazimierczuk K., Sitkowski J., Wietrzyk J. (2019). Similarities and differences in d6 low-spin ruthenium, rhodium and iridium half-sandwich complexes: synthesis, structure, cytotoxicity and interaction with biological targets. J. Biol. Inorg. Chem. 24, 591 – 606. doi:10.1007/s00775-019-01665-2
  29. Guevara Y. A. S., Santos M. H. C., Gomes F. I. R., Mesquita F. P., Souza P. F. N. (2023). A historical, economic, and technical-scientific approach to the current crisis in the development of antibacterial drugs: promising role of antibacterial peptides in this scenario. Microb. Pathog. 179, 106108. doi:10.1016/j.micpath.2023.106108
  30. Guz-Regner K., Komarnicka U. K., Futoma-Kołoch B., Wernecki M., Cal M., Kozieł S. (2020). Antibacterial activity and action mode of Cu(I) and Cu(II) complexes with phosphines derived from fluoroquinolone against clinical and multidrug-resistant bacterial strains. J. Inorg. Biochem. 210, 111124. doi:10.1016/j.jinorgbio.2020.111124
  31. Hailey F. J., Newsom J. H. (1984). Evaluation of Bismuth subsalicylate in relieving symptoms of indigestion. Arch. Intern. Med. 144, 269 – 272. doi:10.1001/archinte.1984.00350140069010
  32. Hartinger C. G., Casini A., Duhot C., Tsybin Y. O., Messori L., Dyson P. J. (2008). Stability of an organometallic ruthenium–ubiquitin adduct in the presence of glutathione: relevance to antitumour activity. J. Inorg. Biochem. 102, 2136 – 2141. doi:10.1016/j.jinorgbio.2008.08.002
  33. Kalaiselvan C. R., Laha S. S., Somvanshi S. B., Tabish T. A., Thorat N. D., Sahu N. K. (2022). Manganese ferrite (MnFe2O4) nanostructures for cancer theranostics. Coord. Chem. Rev. 473, 214809. doi:10.1016/j.ccr.2022.214809
  34. Khadivi-Derakhshan S., Pirouzmand M., Soleymani J., Esrafili M. D. (2025). Mn and Cu complexes of a novel malic acid–cysteine ligand with remarkable ROS scavenging activity. RSC Adv. 15, 22006 – 22017. doi:10.1039/D5RA02118A
  35. Klaimanee E., Nhukeaw T., Saithong S., Ratanaphan A., Phongpaichit S., Tantirungrotechai Y. (2021). Half-sandwich ruthenium (II) p-cymene complexes based on organophosphorus ligands: structure determination, computational investigation, in vitro antiproliferative effect in breast cancer cells and antimicrobial activity. Polyhedron 204, 115244. doi:10.1016/j.poly.2021.115244
  36. Kołoczek P., Skórska-Stania A., Cierniak A., Sebastian V., Komarnicka U. K., Płotek M. (2018). Polymeric micelle-mediated delivery of half-sandwich ruthenium(II) complexes with phosphanes derived from fluoroloquinolones for lung adenocarcinoma treatment. Eur. J. Pharm. Biopharm. 128, 69 – 81. doi:10.1016/j.ejpb.2018.04.016
  37. Komarnicka U. K., Kozieł S., Starosta R., Kyzioł A. (2018). Selective Cu(I) complex with phosphine-peptide (SarGly) conjugate contra breast cancer: synthesis, spectroscopic characterization and insight into cytotoxic action. J. Inorg. Biochem. 186, 162 – 175. doi:10.1016/j.jinorgbio.2018.06.009
  38. Komarnicka U. K., Kozieł S., Skórska-Stania A., Kyzioł A., Tisato F. (2022). Synthesis, physicochemical characterization and antiproliferative activity of phosphino Ru(ii) and Ir(iii) complexes. Dalton Trans. 51, 8605 – 8617. doi:10.1039/D2DT01055K
  39. Kozieł S., Komarnicka U. K., Ziółkowska A., Skórska-Stania A., Pucelik B., Płotek M. (2020). Anticancer potency of novel organometallic Ir(iii) complexes with phosphine derivatives of fluoroquinolones encapsulated in polymeric micelles. Inorg. Chem. Front. 7, 3386 – 3401. doi:10.1039/D0QI00538J
  40. Kozieł S., Wojtala D., Szmitka M., Sawka J., Komarnicka U. K. (2024). Can Mn coordination compounds be good candidates for medical applications? Front. Chem. Biol. 3, 1337372. doi:10.3389/fchbi.2024.1337372
  41. Kozieł S., Wojtala D., Barzowska-Gogola A., Pucelik B., Waglewska E., Siczek M. (2025a). Bilosomal encapsulation of Binuclear phosphino Ru(II)–Cu(II) compounds enhances their selectivity and activity toward lung and prostate cancers. J. Med. Chem. 68, 14442 – 14464. doi:10.1021/acs.jmedchem.5c00486
  42. Kozieł S., Wojtala D., Szmitka M., Lesiów M., Ziółkowska A., Sawka J. (2025b). Half‐sandwich organometallic Ir(III) and Ru(II) compounds and their interactions with biomolecules. Chempluschem 90, e202400621. doi:10.1002/cplu.202400621
  43. Kumar S., Pal Sharma R., Venugopalan P., Singh Gondil V., Chhibber S., Aree T. (2018). Hybrid inorganic-organic complexes: synthesis, spectroscopic characterization, single crystal X-ray structure determination and antimicrobial activities of three copper(II)-diethylenetriamine-p-nitrobenzoate complexes. Inorganica Chim. Acta 469, 288 – 297. doi:10.1016/j.ica.2017.09.032
  44. Kumar Singh A., Kumar A., Singh H., Sonawane P., Pathak P., Grishina M. (2023). Metal complexes in cancer treatment: Journey So far. Chem. Biodivers. 20, e202300061. doi:10.1002/cbdv.202300061
  45. Lee S. P. (1991). The mode of action of colloidal bismuth subcitrate. Scand. J. Gastroenterol. 26, 1 – 6. doi:10.3109/00365529109093213
  46. Lenz G. R., Martell A. E. (1964). Metal chelates of some sulfur-containing amino acids. Biochemistry 3, 745 – 750. doi:10.1021/bi00894a001
  47. Li F., Collins J. G., Keene F. R. (2015). Ruthenium complexes as antimicrobial agents. Chem. Soc. Rev. 44, 2529 – 2542. doi:10.1039/C4CS00343H
  48. Li J., Tian Z., Ge X., Xu Z., Feng Y., Liu Z. (2019). Design, synthesis, and evaluation of fluorine and naphthyridine–based half-sandwich organoiridium/ruthenium complexes with bioimaging and anticancer activity. Eur. J. Med. Chem. 163, 830 – 839. doi:10.1016/j.ejmech.2018.12.021
  49. Lin S., Yu G., Zhang L., Liao X., Jiang G., Liu L. (2025). Multi-target antibacterial Ru-based metallodrugs containing phenylsulfonyl indole derivatives: synthesis and their efficacy against Gram-positive and -negative bacteria. RSC Adv. 15, 21284 – 21299. doi:10.1039/D5RA03098F
  50. Liu J., Yuan Y., Cheng Y., Fu D., Chen Z., Wang Y. (2022). Copper-based metal–organic framework overcomes cancer chemoresistance through systemically disrupting dynamically balanced cellular redox homeostasis. J. Am. Chem. Soc. 144, 4799 – 4809. doi:10.1021/jacs.1c11856
  51. Liu J., Wu Y., Yang G., Liu Z., Liu X. (2023). Mitochondrial targeting half-sandwich iridium(III) and ruthenium(II) dppf complexes and in vitro anticancer assay. J. Inorg. Biochem. 239, 112069. doi:10.1016/j.jinorgbio.2022.112069
  52. Lyra-Leite D. M., Copley R. R., Freeman P. P., Pongpamorn P., Shah D., McKenna D. E. (2023). Nutritional requirements of human induced pluripotent stem cells. Stem Cell Rep. 18, 1371 – 1387. doi:10.1016/j.stemcr.2023.05.004
  53. Martin J. E., Waters L. S. (2022). Regulation of bacterial manganese homeostasis and usage during stress responses and pathogenesis. Front. Mol. Biosci. 9, 945724. doi:10.3389/fmolb.2022.945724
  54. Martins A. C., Oliveira-Paula G. H., Tinkov A. A., Skalny A. V., Tizabi Y., Bowman A. B. (2025). Role of manganese in brain health and disease: focus on oxidative stress. Free Radic. Biol. Med. 232, 306 – 318. doi:10.1016/j.freeradbiomed.2025.03.013
  55. Molinspiration (2026). Molinspiration cheminformatics tools for molecular property calculation and bioactivity prediction. Bratislava: Slovakia. Available online at: (Accessed August 2, 2025).
  56. Munteanu A.-C., Uivarosi V. (2021). Ruthenium complexes in the fight against pathogenic microorganisms. An extensive review. Pharmaceutics 13, 874. doi:10.3390/pharmaceutics13060874
  57. Ogino H., Fujii M., Ono M., Maezawa K., Kizu J., Hori S. (2009). In vivo and in vitro effects of fluoroquinolones on lipopolysaccharide-induced pro-inflammatory cytokine production. J. Infect. Chemother. 15, 168 – 173. doi:10.1007/s10156-009-0680-1
  58. O’Reilly C., Blasco S., Parekh B., Collins H., Cooke G., Gunnlaugsson T. (2021). Ruthenium-centred btp glycoclusters as inhibitors for Pseudomonas aeruginosa biofilm formation. RSC Adv. 11, 16318 – 16325. doi:10.1039/D0RA05107A
  59. Petrauskas A., Kolovanov E. A. (2000). ACD/Log P method description. Perspect. Drug Discov. Des. 18, 19 – 38. doi:10.1023/A:1008740722750
  60. Romanowski S. M. de M., Machado S. P., Friedermann G. R., Mangrich A. S., Hermann M. de F., Lima H. O. (2010). Synthesis, characterization, EPR spectroelectrochemistry studies and theoretical calculations of manganese(II) complexes with the ligands H3bpeten and H3bnbpeten. J. Braz. Chem. Soc. 21, 842 – 850. doi:10.1590/S0103-50532010000500011
  61. Ruhal R., Kataria R. (2021). Biofilm patterns in gram-positive and gram-negative bacteria. Microbiol. Res. 251, 126829. doi:10.1016/j.micres.2021.126829
  62. Sadeek S. A. (2005). Synthesis, thermogravimetric analysis, infrared, electronic and mass spectra of Mn(II), Co(II) and Fe(III) norfloxacin complexes. J. Mol. Struct. 753, 1 – 12. doi:10.1016/j.molstruc.2005.06.011
  63. Si M., Zhao C., Burkinshaw B., Zhang B., Wei D., Wang Y. (2017). Manganese scavenging and oxidative stress response mediated by type VI secretion system in Burkholderia thailandensis. Proc. Natl. Acad. Sci. 114, E2233-E2242. doi:10.1073/pnas.1614902114
  64. Šimėnas M., Ciupa A., Mączka M., Völkel G., Pöppl A., Banys J. (2016). EPR of structural phase transition in Manganese- and copper-doped formate framework of [NH 3 (CH 2) 4 NH 3 ] [Zn(HCOO) 3 ] 2. J. Phys. Chem. C 120, 19751 – 19758. doi:10.1021/acs.jpcc.6b07389
  65. Smitten K. L., Scattergood P. A., Kiker C., Thomas J. A., Elliott P. I. P. (2020). Triazole-based osmium(II) complexes displaying red/near-IR luminescence: antimicrobial activity and super-resolution imaging. Chem. Sci. 11, 8928 – 8935. doi:10.1039/D0SC03563G
  66. Tamer Ö. (2017). A unique manganese (II) complex of 4-methoxy-pyridine-2-carboxylate: synthesis, crystal structure, FT-IR and UV–Vis spectra and DFT calculations. J. Mol. Struct. 1144, 370 – 378. doi:10.1016/j.molstruc.2017.05.077
  67. Tanifuji K., Ohta S., Ohki Y., Seino H. (2023). Activation of unsaturated small molecules by bio-relevant multinuclear metal-sulfur clusters. Coord. Chem. Rev. 475, 214838. doi:10.1016/j.ccr.2022.214838
  68. Tetko I. V., Tanchuk V.Yu. (2002). Application of associative neural networks for prediction of lipophilicity in ALOGPS 2.1 program. J. Chem. Inf. Comput. Sci. 42, 1136 – 1145. doi:10.1021/ci025515j
  69. Thangamani S., Mohammad H., Abushahba M. F. N., Sobreira T. J. P., Hedrick V. E., Paul L. N. (2016). Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens. Sci. Rep. 6, 22571. doi:10.1038/srep22571
  70. Uivarosi V. (2013). Metal complexes of quinolone antibiotics and their applications: an update. Molecules 18, 11153 – 11197. doi:10.3390/molecules180911153
  71. Vechalapu S. K., Kumar R., Sachan S. K., Shaikh K., Mahapatra A. D., Draksharapu A. (2024). Copper and manganese complexes of pyridinecarboxaldimine induce oxidative cell death in cancer cells. ACS Appl. Bio Mater. 7, 6696 – 6705. doi:10.1021/acsabm.4c00854
  72. Wang C., Wei X., Zhong L., Chan C.-L., Li H., Sun H. (2025). Metal-based approaches for the fight against antimicrobial resistance: mechanisms, opportunities, and challenges. J. Am. Chem. Soc. 147, 12361 – 12380. doi:10.1021/jacs.4c16035
  73. Wang L., Liu L., Wang X., Tan Y., Duan X., Zhang C. (2022). Ruthenium(II) complexes targeting membrane as biofilm disruptors and resistance breakers in Staphylococcus aureus bacteria. Eur. J. Med. Chem. 238, 114485. doi:10.1016/j.ejmech.2022.114485
  74. Wang L.-H., Tai X.-S., Azam M., Sui B.-L., Wang A.-L. (2025). Synthesis, structural characterization, and hirschfeld surface analysis of a novel Mn(II) complex based on N-acetyl-L-phenylalanine ligand and its evaluation as a cytotoxic agent. Polyhedron 279, 117659. doi:10.1016/j.poly.2025.117659
  75. Wojtala D., Kozieł S., Witwicki M., Niorettini A., Guz‐Regner K., Bugla‐Płoskońska G. (2023). Antibactericidal Ir(III) and Ru(II) complexes with phosphine‐alkaloid conjugate and their interactions with biomolecules: a case of N ‐methylphenethylamine. Chem. – A Eur. J. 29, e202301603. doi:10.1002/chem.202301603
  76. Woźnicka E., Miłoś A., Zapała L., Kosińska-Pezda M., Ciszkowicz E., Byczyński Ł. (2026). Synthesis, spectroscopic, and photophysical studies of Mn(II), Co(II), and Zn(II) complexes with 3-hydroxyflavone: insights into anticancer activity against prostate cancer cells. J. Inorg. Biochem. 274, 113084. doi:10.1016/j.jinorgbio.2025.113084
  77. Xiao J., Högger P. (2015). Stability of dietary polyphenols under the cell culture conditions: avoiding erroneous conclusions. J. Agric. Food Chem. 63, 1547 – 1557. doi:10.1021/jf505514d
  78. Zhang H. L., Wang M. L., Yi L. Z., Högger P., Arroo R., Bajpai V. K. (2022). Stability profiling and degradation products of dihydromyricetin in Dulbecco’s modified eagle’s medium. Food Chem. 378, 132033. doi:10.1016/j.foodchem.2021.132033
  79. Zhao S., Adamiak J. W., Bonifay V., Mehla J., Zgurskaya H. I., Tan D. S. (2020). Defining new chemical space for drug penetration into Gram-negative bacteria. Nat. Chem. Biol. 16, 1293 – 1302. doi:10.1038/s41589-020-00674-6
  80. Zheng R., Guo J., Cai X., Bin L., Lu C., Singh A. (2022). Manganese complexes and manganese-based metal-organic frameworks as contrast agents in MRI and chemotherapeutics agents: applications and prospects. Colloids Surf. B Biointerfaces 213, 112432. doi:10.1016/j.colsurfb.2022.112432

Citation

Wojtala, D., et al. (2026). Antibacterial potential of mono- Ru(II) and bi-metallic Ru(II)-Mn(II) inorganic compounds with phosphino-fluoroquinolone conjugates. Frontiers in Chemical Biology, Volume 5. https://doi.org/
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5 - 2026

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Copyright © 2026 Wojtala, Kozieł, Łoś, Guz-Regner, Lesiów, Szmitka, Kardas, Bajkowski, Bugla-Płoskońska and Komarnicka.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Sandra Kozieł; Urszula K. Komarnicka

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