Unraveling mechanistic differences and similarities in resistance profiles to antimicrobial peptides and conventional antibiotics

1 Introduction

Antimicrobial resistance (AMR) represents one of the most significant threats to global public health in the 21^st century. The rapid emergence and dissemination of multidrug-resistant bacteria have progressively reduced the effectiveness of conventional therapies, leading to increased morbidity, mortality, and healthcare costs (Priya and de Carvalho, 2026). Estimates from the Global Burden of Disease AMR project indicate that bacterial AMR was associated with approximately 4.71 million deaths worldwide in 2021 (Naghavi et al., 2024). In addition, the latest report from the World Health Organization Global Antimicrobial Resistance and Use Surveillance System indicates that, among laboratory-confirmed bacterial infections reported in 2023, approximately one in six were resistant to antibiotic treatment. Moreover, resistance increased in more than 40% of monitored pathogen-antibiotic pairs between 2018 and 2023 (WHO, 2025), reinforcing the urgency of mechanistic and evolutionary investigations in this field.

From a mechanistic perspective, the emergence and dissemination of AMR are intrinsically linked to the selective pressure exerted by currently used therapeutic agents. Exposure to these compounds creates an environment in which susceptible bacteria are inhibited or eradicated, while resistant variants survive and proliferate (Brepoels et al., 2025). Within this process of natural selection, the intensity, duration, and concentration of antimicrobial exposure shape resistance trajectories, influencing which genetic and adaptive pathways are favored (Maeda and Furusawa, 2024). Notably, different classes of antimicrobial agents may impose qualitatively distinct selective pressures depending on their mechanisms of action, pharmacodynamic properties, and the bacterial responses they elicit. Understanding how these pressures translate into specific resistance phenotypes is essential for predicting and mitigating the spread of multidrug-resistant organisms (Salam et al., 2023).

Conventional antibiotics comprise a chemically diverse group of low-molecular-weight molecules, including β-lactams, aminoglycosides, quinolones, tetracyclines, and macrolides (Bergkessel et al., 2023). These compounds exert bactericidal or bacteriostatic effects by interacting with defined molecular targets that mediate essential cellular processes, such as cell wall biosynthesis, protein translation, nucleic acid replication, and core metabolic pathways (Baran et al., 2023). This high degree of target specificity has been central to their clinical success, enabling potent and predictable therapeutic outcomes across a wide range of bacterial infections. However, the same specificity also imposes strong and directional selective pressure on microbial populations (Gauba and Rahman, 2023). Consequently, the widespread use and misuse of antibiotics over decades have been accompanied by the relentless emergence and global dissemination of resistance, often driven by stable genetic adaptations that can be efficiently transmitted across bacterial populations (Hossain and Chowdhury, 2024).

In parallel, antimicrobial peptides (AMPs) have attracted increasing attention as promising alternatives or complements to conventional antibiotics. These molecules are evolutionarily ancient components of the innate immune system and are broadly distributed across eukaryotic and prokaryotic organisms, displaying activity against bacteria, fungi, and viruses (Baseer et al., 2025). Typically, AMPs consist of 5 to 50 amino acid residues and exhibit cationic and amphipathic properties that promote electrostatic interactions with negatively charged bacterial membranes (Satchanska et al., 2024). As a result, many AMPs exert their antimicrobial effects by compromising membrane integrity, ultimately leading to cell death. Moreover, several peptides can translocate across the membrane and interact with intracellular targets, further contributing to their multifaceted modes of action (Kr et al., 2024). This mechanistic diversity suggests that bacterial responses to AMPs may differ from those observed for conventional antibiotics. Nevertheless, reduced susceptibility to AMPs is neither rare nor negligible, as bacteria have developed diverse adaptive strategies that collectively diminish peptide activity (Yu et al., 2025).

Therefore, whereas resistance to antibiotics is often associated with well-defined genetic alterations, enzymatic inactivation, and the dissemination of mobile genetic elements (Bobate et al., 2023), reduced susceptibility to AMPs frequently involves envelope remodeling, activation of stress-response pathways, and regulatory adaptation (Tajer et al., 2024). Although the individual mechanisms underlying resistance to antibiotics and AMPs have been extensively characterized, these processes are commonly investigated in isolation. Consequently, important questions remain regarding how these antimicrobial classes compare in terms of the nature, stability, and evolutionary dynamics of the resistance they elicit.

Accordingly, this mini review aims to provide an integrated perspective by examining bacterial evasion mechanisms against both conventional antibiotics and AMPs. By contrasting their molecular targets, cellular responses, and evolutionary trajectories, we seek to shed light over mechanistic differences and similarities that shape resistance emergence and persistence, thereby contributing to ongoing discussions on strategies to preserve the long-term effectiveness of current and future antimicrobial therapies.

2 Conventional antibiotics: mechanisms of action and resistance

Antibiotics exert their clinical efficacy through highly specific interactions with essential bacterial processes (Figure 1A), primarily targeting the cell wall, the ribosome, or key enzymes involved in nucleic acid metabolism (Greve and Cowan, 2022). While this molecular precision underlies their therapeutic success, it also defines the evolutionary landscape in which resistance emerges. Among structural targets, the peptidoglycan layer of the bacterial cell wall remains one of the most extensively exploited. β-lactam antibiotics inhibit the transpeptidation activity of penicillin-binding proteins (PBPs), thereby preventing glycan cross-linking and compromising cell wall integrity, leading to bacterial lysis (Darby et al., 2023; Halawa et al., 2024).

Beyond the cell envelope, the translational machinery constitutes another major target of antimicrobial action. Aminoglycosides initially interact with negatively charged membrane components, promoting destabilization and uptake, before binding to the 30S ribosomal subunit to induce mRNA misreading and inhibit protein synthesis (Dey et al., 2025; Greve and Cowan, 2022; Halawa et al., 2024). Tetracyclines similarly target the 30S subunit by preventing aminoacyl-tRNA binding, whereas macrolides, lincosamides, oxazolidinones, and phenicols bind to the 50S subunit to impair peptide elongation (Halawa et al., 2024; Sultan et al., 2018; Wilson et al., 2020). Additional antibiotic classes interfere with nucleic acid metabolism. In this regard, quinolones and fluoroquinolones inhibit DNA gyrase and topoisomerase IV, generating lethal double-strand breaks, while rifamycins suppress transcription through inhibition of DNA-dependent RNA polymerase (Darby et al., 2023; Hardie and Fenn, 2022). Likewise, sulfonamides and pyrimidines disrupt folate metabolism, impairing nucleotide biosynthesis and bacterial proliferation (Halawa et al., 2024; Ovung and Bhattacharyya, 2021).

The same site-specificity that confers efficacy also imposes intense selective pressure on conserved binding sites, facilitating adaptive responses (Darby et al., 2023; Greve and Cowan, 2022). Because antibiotic activity depends on precise molecular interactions, even subtle structural alterations can markedly reduce drug affinity without compromising essential cellular functions (Darby et al., 2023; Sultan et al., 2018). Consequently, resistance frequently arises through predictable molecular solutions (Figure 1B). Target modification is a central strategy, ranging from site-specific rRNA methylation, such as N1-methylation of adenine 1408 (m¹A1408) in 16S rRNA, which sterically hinders aminoglycoside binding (Dey et al., 2025), to large-scale remodeling events. The acquisition of mecA in methicillin-resistant Staphylococcus aureus (MRSA), for instance, encodes the low-affinity PBP2a, enabling continued peptidoglycan synthesis despite β-lactam exposure (Munita and Arias, 2016).

In parallel, bacteria use complementary mechanisms that preserve target function while neutralizing antibiotic activity. Ribosomal protection proteins such as Tet(M) and Tet(O) displace tetracyclines from the 30S subunit, whereas FusB-type proteins release fusidic acid from elongation factor G (Wilson et al., 2020). Enzymatic inactivation provides a more direct countermeasure. For instance, β-lactamases, including AmpC variants, hydrolyze the β-lactam ring and confer resistance in organisms such as Pseudomonas aeruginosa (Barceló et al., 2022), while chloramphenicol acetyltransferases reduce drug affinity for the 50S subunit in MRSA (Wang K. et al., 2025). The widespread distribution of these enzymes on mobile genetic elements underscores their integration into the global resistome (Peterson and Kaur, 2018; Sultan et al., 2018).

Further, resistance is reinforced by limiting intracellular drug accumulation. In Gram-negative bacteria, outer membrane permeability is restricted by lipopolysaccharide composition and selective porins. Thus, adaptive changes such as loop 3 insertions in OmpK36 from Klebsiella pneumoniae reduce carbapenem susceptibility (Akshay et al., 2023; Maher and Hassan, 2023; Wong et al., 2019). Reduced permeability frequently operates in concert with active efflux systems, as illustrated by the MmpL (MAB_2303) efflux pump in Mycobacterium abscessus, whose deletion increases susceptibility to linezolid (McGowen et al., 2025).

Beyond these molecular adaptations, the evolutionary success and persistence of antibiotic resistance are profoundly determined by the interplay between vertical inheritance and horizontal gene transfer (HGT). Chromosomal mutations conferring resistance can be spread stably through clonal expansion under sustained selective pressure (Darby et al., 2023). Nonetheless, the global dissemination of resistance is largely driven by mobile genetic elements that mobilize and redistribute antibiotic resistance genes (ARGs) across taxonomic and ecological boundaries. Large-scale genomic analyses reveal that a substantial fraction of clinically relevant ARGs are embedded within gene exchange networks that span multiple bacterial phyla and frequently link Gram-positive and Gram-negative species (Ellabaan et al., 2021). This extensive phylogenetic reach underscores the central role of plasmids, transposons, and integrative elements in capturing and amplifying resistance determinants.

It is worth noting that plasmids are not merely vectors of gene transfer but dynamic evolutionary elements. Their multicopy nature, capacity for rapid adaptation, and ability to engage in compensatory evolution can mitigate the fitness costs often associated with resistance acquisition, thereby promoting long-term stability even in fluctuating antibiotic environments (Rodríguez-Beltrán et al., 2021). Compensatory mutations in plasmid or chromosomal backgrounds may stabilize resistance traits, enabling their persistence in the absence of continuous drug exposure. Collectively, these processes establish a multilayered evolutionary framework in which resistance can arise via mutation, consolidate through vertical selection, and disseminate through horizontal transfer across populations and ecosystems. This evolutionary plasticity underpins the durability and global spread of conventional antibiotic resistance and provides a critical mechanistic baseline for evaluating alternative antimicrobial strategies.

3 Antimicrobial peptides: mechanisms of action and resistance

The slow pace of new antibiotic discovery, along with the rapid emergence of AMR, has significantly intensified the challenge of developing effective therapies (Liu et al., 2024; Mohapatra et al., 2021). AMPs are a structurally diverse group of molecules widely distributed across living organisms, including eukaryotes, bacteria, and archaea, where they play a central role in innate immunity and host defense. As key components of the innate immune response, AMPs exhibit broad biological activity against a wide range of pathogenic agents, including bacteria, fungi, viruses, protozoa, and even certain toxins, highlighting their functional versatility and biological relevance in protecting the host (Cardoso et al., 2020; Oliveira Júnior et al., 2025). In contrast to conventional antibiotics, AMPs differ substantially in their pharmacodynamic behavior (Yu et al., 2018). These differences reinforce their potential as alternative therapeutic agents in the context of AMR. Owing to their high specificity and distinct modes of action, AMPs generally exert antimicrobial effects in ways that limit the emergence of resistance and reduce the probability of mutation-driven adaptation, positioning them as promising candidates for addressing drug-resistant infections (Oliveira Júnior et al., 2025; Yu et al., 2018).

Structurally, AMPs adopt several scaffolds and are commonly categorized into five major groups (e.g., linear extended peptides, helical-structured peptides, β-structured peptides, mixed α/β elements, and cyclic or complex topologies) (Oliveira Júnior et al., 2025). Linear extended AMPs typically lack a fixed secondary structure and rely on flexibility inducer residues, including glycine and proline, enabling them to interact with microbial membranes and penetrate cells. Helical peptides form amphipathic helices stabilized by hydrogen bonds, allowing selective membrane disruption. β-structured AMPs contain β-strands usually stabilized by disulfide bonds, conferring stability and facilitating binding to bacterial membranes. Moreover, mixed α/β peptides combine flexibility and stability to enhance antimicrobial efficacy. Finally, cyclic AMPs have a covalently closed backbone that forms a continuous loop structure. This structural scaffold increases structural stability and resistance to proteolytic degradation compared to linear peptides. These diverse structural arrangements underlie the versatility of AMPs in recognizing and neutralizing a broad spectrum of pathogens (Oliveira Júnior et al., 2025).

AMPs employ a variety of mechanisms to exert their antimicrobial effects (Figure 1A), with membrane disruption being the most well-characterized (Nayab et al., 2022; Oliveira Júnior et al., 2025). Many AMPs are cationic and amphipathic, allowing them to associate with negatively charged bacterial membranes. Upon reaching a threshold concentration, they insert into the lipid bilayer, inducing pore formation or destabilizing the membrane structure, which results in leakage of vital cytoplasmic components and ultimately cell lysis. This disruption can occur via multiple models, including barrel-stave, toroidal pore, or carpet models, each describing different arrangements and interactions of peptides with the membrane (Nayab et al., 2022; Oliveira Júnior et al., 2025). Some AMPs, including magainins and cecropins, form transmembrane channels that disturb ion gradients, leading to loss of membrane potential and metabolic collapse. Additionally, certain peptides can translocate through the membrane to target intracellular structures without causing outright membrane rupture, thus providing an alternative mechanism of microbial killing that can be particularly effective against bacteria with more resistant cell envelopes, including Gram-negative species (Nayab et al., 2022; Oliveira Júnior et al., 2025).

Apart from direct membrane interaction, many AMPs target intracellular components essential for microbial survival and replication, expanding their antimicrobial arsenal. They can penetrate the cell and bind to nucleic acids, including DNA and RNA, inhibiting replication, transcription, or translation (Nayab et al., 2022; Oliveira Júnior et al., 2025). Others inhibit key enzymes involved in DNA replication or repair, including DNA gyrase or topoisomerases, thereby impairing bacterial proliferation. Certain AMPs also interfere with vital processes such as protein folding by targeting molecular chaperones (e.g., DnaK or GroEL) or disrupt bacterial metabolic pathways by inhibiting enzymes necessary for biosynthesis or energy production. Moreover, some peptides can modulate signaling pathways or induce apoptosis-like programmed cell death mechanisms within microbes. These intracellular actions provide a multifaceted approach to antimicrobial activity, reduce the potential for resistance development, and highlight the versatility of AMPs as therapeutic agents (Nayab et al., 2022; Oliveira Júnior et al., 2025).

Despite their promising antimicrobial properties, even with less probability of mutation-driven adaptation, bacteria have evolved multiple strategies to resist the antimicrobial action of AMPs (Oliveira Júnior et al., 2025; Yu et al., 2018). Bacterial resistance to AMPs is typically achieved through a variety of complex strategies that modify cell surface properties and employ active defense mechanisms (Figure 1B). One prevalent mechanism involves modifications to the bacterial membrane that reduce its negative charge, thereby diminishing electrostatic attraction between cationic AMPs and the bacterial surface (Cardoso et al., 2017; Oliveira Júnior et al., 2025). For Gram-negative bacteria, this often includes the addition of molecules like 4-amino-4 deoxy-L-arabinose or phosphoethanolamine to the lipid A portion of lipopolysaccharides. In Gram-positive bacteria, resistance can involve enhanced D-alanylation of teichoic acids, altering cell wall charge and hydrophobicity, or changes in membrane phospholipid composition. Additionally, some bacteria produce enzymes such as nisinase to degrade specific AMPs or utilize ABC transporters to actively efflux peptides, further reducing effective intracellular concentrations and antimicrobial potency (Cardoso et al., 2017; Oliveira Júnior et al., 2025).

Beyond membrane alterations, bacteria employ other adaptive strategies to evade AMP activity (which are similar to those reported for conventional antibiotics), including the production of protective extracellular structures, including capsules, biofilms, and outer membrane vesicles that serve as physical barriers, limiting peptide access to the cell surface (Cardoso et al., 2017; Oliveira Júnior et al., 2025). These structures mimic membrane components and can sequester AMPs, reducing their availability to interact with critical targets. Furthermore, bacteria can regulate the expression of outer membrane proteins, including OprH, to enhance resistance to peptide antibiotics like polymyxins (Oliveira Júnior et al., 2025). Moreover, genetic adaptations, including mutations or modifications to target molecules and regulation of membrane protein expression, contribute to an array of resistance mechanisms. Collectively, these multifaceted strategies highlight the remarkable ability of bacteria to adapt and survive in hostile environments where AMPs are present, posing ongoing challenges for antimicrobial therapy (Cardoso et al., 2017; Oliveira Júnior et al., 2025).

Polymyxins, a class of lipopeptides discovered in the 1940s, were widely used to treat infections caused by Gram-negative bacteria for decades. However, due to their severe nephrotoxicity and neurotoxicity, their use was largely discontinued in the 1980s (Falagas and Michalopoulos, 2006). The emergence of Gram-negative bacteria with extreme resistance to nearly all major classes of antibiotics led to the reintroduction of polymyxin therapy, making polymyxins a last-resort treatment (Falagas and Michalopoulos, 2006; Liu et al., 2024; Mohapatra et al., 2021). Advances in technology and science have enabled chemical modifications of polymyxins and the development of new derivatives. These, combined with optimized dosing regimens, have significantly reduced their toxic effects (Liu et al., 2024; Mohapatra et al., 2021). However, the emergence of polymyxin-resistant bacteria has already been documented in recent literature (Li et al., 2019).

Resistance mechanisms for polymyxin E, also known as colistin, include modifications to the bacterial outer membrane, such as the addition of phosphoethanolamine to lipid A, which diminishes colistin’s ability to bind and disrupt the bacterial outer membrane (Ahn et al., 2025; Li et al., 2019). Of great concern is the plasmid-mediated mcr-1 gene, which encodes an enzyme responsible for these modifications and can spread rapidly across bacterial populations through horizontal gene transfer. The widespread presence of such resistance genes has led to the emergence of bacterial strains that can withstand colistin treatment, thereby compromising treatment options for severe infections caused by multidrug-resistant Gram-negative pathogens (Ahn et al., 2025; Li et al., 2019).

Apart from the acquired resistance profiles described above, it is important to recognize that bacteria can also exhibit intrinsic mechanisms of resistance to AMPs. In the case of polymyxin B, for example, Neisseria meningitidis displays high intrinsic resistance due to the expression of a capsular polysaccharide encoded by the siaD gene, which mechanistically protects the bacteria by impairing AMP-membrane interactions (Spinosa et al., 2007). Notably, siaD-deficient mutants are highly susceptible not only to polymyxin B but also to a broad range of AMPs, including defensins, cathelicidins, and protegrins, underscoring the central role of this gene in intrinsic AMP resistance (Spinosa et al., 2007). Similarly, biofilm formation on biotic and abiotic surfaces represents a major challenge in combating AMR. Biofilms are widely recognized as an intrinsic resistance mechanism, conferring protection against multiple antimicrobial agents, including AMPs (Joo et al., 2016). In addition, certain Gram-negative enteric pathogens, such as E. coli and Salmonella enterica, exhibit intrinsic resistance to AMPs associated with the expression of specific genes, including envC and zapB (Oguri et al., 2016). In particular, envC has been implicated in multiple cellular processes and is essential for bacterial physiology in species such as P. aeruginosa and Haemophilus influenzae, while also influencing virulence factors in S. enterica (Oguri et al., 2016).

Another important aspect to consider when discussing intrinsic and acquired bacterial resistance to conventional antibiotics and AMPs is that agents from both classes can be used in combination therapy to achieve synergistic effects (Gonçalves et al., 2025). Such strategies, particularly against Gram-negative pathogens, are typically justified by three main objectives: (i) to minimize or delay the emergence of resistance during antimicrobial treatment; (ii) to broaden empirical antimicrobial coverage by combining agents with distinct spectra of activity, thereby increasing the likelihood that the causative pathogen is effectively targeted by at least one component of the regimen; and (iii) to exploit synergistic interactions observed in vitro between antimicrobial agents in order to enhance therapeutic efficacy and improve clinical outcomes (Gonçalves et al., 2025). However, despite being promising and well documented in the literature, synergy between antibiotics and AMPs remains controversial due to potential drawbacks, including superinfection, antagonistic interactions, adverse effects, and the possible evolution of bacterial resistance. The latter is particularly concerning, as combination therapies may involve the use of antimicrobial agents at sublethal concentrations and with distinct pharmacokinetic and pharmacodynamic profiles, which can directly influence their effectiveness at the site of infection (Gonçalves et al., 2025).

4 Comparative analysis of resistance profiles

The foundation for understanding the resistance profiles lies in the pharmacodynamic properties of each antimicrobial class (Table 1). Conventional antibiotics are characterized by high-affinity interactions with evolutionarily conserved molecular targets that mediate essential cellular processes (Uddin et al., 2021). This specific “lock-and-key” mechanism creates an intense and directional selective pressure that favors discrete genetic alterations capable of subverting the drug-target interaction (Berger and Loewy, 2024). By contrast, the primary activity of most AMPs is governed by cumulative physicochemical interactions with the bacterial envelope, a structurally dynamic cellular compartment (Pirtskhalava et al., 2021). Therefore, the selective pressure exerted by AMPs is less target-restricted, favoring not a single genetic event but rather a suite of physiological adaptations that collectively reduce membrane susceptibility (Zhang et al., 2021). This fundamental difference in selective stimulus shapes the nature of the bacterial response, as the former favors the acquisition of discrete genetic determinants, whereas the latter promotes coordinated physiological reprogramming (Yu et al., 2025).

Table 1. Comparative overview of resistance profiles to conventional antibiotics and antimicrobial peptides.

However, this distinction is not absolute, as both antimicrobial classes exhibit secondary interactions that contribute to their overall activity. Several AMPs can translocate across membranes and interfere with intracellular processes, including nucleic acid synthesis, protein folding, metabolic regulation, and the maintenance of electrochemical gradients (Kr et al., 2024; Vanzolini et al., 2022). Likewise, some conventional antibiotics also exert secondary effects beyond their primary molecular targets, including the induction of oxidative stress, membrane perturbation, metabolic rewiring, activation of the SOS response, and the modulation of global stress-response pathways (Pancu et al., 2021). Importantly, these overlapping mechanistic features do not abolish the fundamental differences in the dominant selective pressures imposed by each antimicrobial class (Baquero et al., 2024). Rather, they highlight that resistance evolution is shaped by the integrated physiological stress experienced by the bacterial cell, which is also reflected in pharmacodynamic behavior (Roemhild et al., 2022).

In this context, many AMPs display steeper dose–response relationships, often associated with relatively high Hill coefficients, reflecting a cooperative pharmacodynamic response driven by membrane-disruptive mechanisms. These characteristics generate threshold-like killing dynamics once a critical concentration is reached (Chen et al., 2023; Farfán-García et al., 2025). By contrast, the pharmacodynamic curves of conventional antibiotics often exhibit lower or intermediate Hill coefficients, reflecting a more progressive relationship between target occupancy and growth inhibition, although considerable variability exists across drug classes (Gubenšek et al., 2022). Consequently, the architecture of dose–response curves itself becomes an evolutionary determinant, modulating both the strength and the accessibility of resistance pathways (Angermayr et al., 2022).

As explained above, pharmacodynamic profiles of susceptible and resistant bacterial strains can be used to illustrate the selection of resistance under treatment with a range of dosage. This approach is grounded in the concept of the “mutant selection window” (MSW) (Yu et al., 2018). The MSW framework has been effectively validated in animal models, highlighting its utility for understanding the emergence of resistance under in vivo conditions. As observed for the pharmacodynamic curves discussed above, the width of the MSW is partially influenced by the steepness of these curves (Yu et al., 2018). Specifically, the concentration interval spanning from no bacterial killing to maximal killing is considerably narrower for AMPs than for conventional antibiotics, resulting in a steeper pharmacodynamic profile (Fantner et al., 2010). In addition, AMPs typically exhibit higher maximum killing rates, which are reflected in faster bacterial killing kinetics. These pharmacodynamic differences between AMPs and antibiotics play a key role in defining the size of the MSW and provide a framework for evaluating its impact on the evolution of AMR (Yu et al., 2018).

Taken together, these pharmacodynamic features indicate that the key distinction between antimicrobial resistance profiles lies not in the exclusivity of their mechanisms, but in the nature of the adaptive trajectories they preferentially select (Yu et al., 2025). This can be heuristically framed as a tendency toward predominantly genotypic resistance to conventional antibiotics and predominantly phenotypic resistance to AMPs (Elbediwi and Rolff, 2024). Resistance to antibiotics typically manifests as a stable genetic trait, involving the acquisition of genes encoding drug-modifying enzymes, mutations that preclude target binding, or the evolution of highly specific efflux systems (Darby et al., 2022; Galgano et al., 2025). Consequently, the discrete nature of these mechanisms means that resistance can be gained or lost in single genetic events, and its heritability is robust (Nasrollahian et al., 2024). Furthermore, the frequent localization of these determinants on mobile genetic elements facilitates their rapid horizontal dissemination (Jian et al., 2021). Conversely, reduced susceptibility to AMPs is rarely achieved through a single, highly specialized resistance gene. Instead, it arises from the activation of global stress response systems that coordinately remodel envelope architecture (Murtha et al., 2024). These include modifications that reduce the net negative charge of the cell surface through alterations in surface polymers, adjustments in membrane fluidity via changes in lipid composition, and the upregulation of envelope-associated proteases (Murtha et al., 2024; Rommelaere et al., 2024).

Despite this conceptual contrast (Table 1), the two resistance paradigms share important mechanistic features that reveal a more nuanced reality. Efflux mechanisms, for instance, represent a clear point of convergence (Ghoshal et al., 2023). While some efflux pumps exhibit remarkable specificity for a particular antibiotic class, other systems can accommodate a broad range of structurally distinct substrates, including both conventional antibiotics and certain AMPs (Lorusso et al., 2022). A further similarity lies in the modification of the antimicrobial target itself. Although the specific targets differ fundamentally (an essential enzyme for antibiotics versus the phospholipid bilayer for AMPs), the underlying principle of altering the target’s structure or accessibility to reduce drug binding is conceptually analogous (Tajer et al., 2024). Regarding AMPs, this involves changing the biophysical properties of the membrane, whereas for antibiotics, it typically involves a point mutation in a protein-encoding gene (Darby et al., 2022; Li et al., 2021). Moreover, both classes of antimicrobials are subject to resistance mediated by the envelope acting as a permeability barrier (Elshobary et al., 2025). For instance, reductions in porin expression can limit the entry of multiple antibiotic classes, while similar modifications to outer membrane composition can impede AMP access to the cytoplasmic membrane (Maher and Hassan, 2023; Zhou et al., 2023). These convergences suggest that while the primary adaptive strategies may differ, the bacterial repertoire for combating antimicrobial stress draws upon a shared set of physiological and structural resources (Song, 2024).

A direct and consequential outcome of the antimicrobial adaptive bases is a clear divergence in their resistant phenotype stability, particularly in the absence of selective pressure (Table 1). The genotypic nature of antibiotic resistance confers long-term persistence, as resistance genes can be maintained even when the corresponding drug is withdrawn (Javvadi and Mohan, 2024; Zhu et al., 2022). This heritability, especially when genes are linked to mobile elements or have minimal fitness costs, explains the widespread persistence of resistance determinants in bacterial reservoirs long after antibiotic use has been discontinued (Wang et al., 2024; Zhu et al., 2022). By contrast, the predominantly phenotypic and metabolically costly adaptations that confer reduced susceptibility to AMPs are often rapidly reversed in an AMP-free environment (Mekdessi et al., 2025). The constitutive activation of energy-intensive stress responses or the chronic remodeling of membrane composition imposes a fitness burden, creating a strong selective drive to revert to the energetically favorable wild-type state (Maron et al., 2022; Mekdessi et al., 2025). This partial reversibility suggests that resistance to AMPs may be a more dynamic and transient state, fluctuating with the presence of the selective pressure (Zhang et al., 2021).

Despite these mechanistic contrasts, resistance to both antibiotics and AMPs arise through selection acting on phenotypic variation within bacterial populations (Tajer et al., 2024). The likelihood that adaptive variants will emerge and become fixed depends on the intensity, duration, and heterogeneity of antimicrobial exposure, particularly in spatially structured environments such as biofilms or host tissues, where antimicrobial gradients shape localized selection dynamics (Morales-Durán et al., 2025). Furthermore, the apparent dichotomy between “specific genetic resistance” and “global physiological adaptation” is not absolute. Even target-site mutations conferring antibiotic resistance are frequently accompanied by metabolic adjustments and stress-response activation that stabilize the phenotype (Lopatkin et al., 2021). Conversely, sustained AMP exposure can select mutations in regulatory systems that constitutively activate protective pathways, converting initially plastic responses into genetically stabilized traits (Georgieva et al., 2022). Thus, resistance should be conceptualized as a continuum shaped by selection, genetic background, and ecological context (Bustamante et al., 2024; Shepherd et al., 2024).

These differences and partial convergences have profound implications for the ecological and evolutionary trajectories of resistance (Table 1). Firstly, the stable genetically encoded nature of antibiotic resistance means that even intermittent drug exposure can maintain resistance genes in a population (Sulaiman and Lam, 2021). Moreover, the phenomenon of co-selection, whereby the use of one antibiotic inadvertently maintains a pool of resistance genes linked on a mobile element, is a major driver of multidrug resistance (Feng et al., 2025). Conversely, the dynamic nature of AMP resistance suggests a potentially different evolutionary pattern, where the high fitness cost of the resistant state may limit its long-term maintenance (Yu et al., 2025). This introduces an evolutionary trade-off, where bacterial populations must constantly balance protection against the peptide with their metabolic efficiency (Sabri et al., 2025).

Beyond resistance itself, the consequences of these adaptive strategies are not restricted to antimicrobial resistance but may also influence bacterial performance across ecological and host-associated contexts (Zhang et al., 2025). The envelope modifications selected by AMPs, even if transient, may inadvertently enhance bacterial fitness in other niches, such as during host colonization, by increasing resistance to host-derived innate immune effectors (Barber and Fitzgerald, 2024). Additionally, the genetic linkage between regulators of AMP resistance and other adaptive traits on mobile elements, an area of growing research, could theoretically render AMP resistance more stable and transmissible than traditionally assumed, echoing the co-selection dynamics well-established for antibiotics (Tokuda and Shintani, 2024). Moreover, adaptations to either antimicrobial class may produce pleiotropic effects, including cross-resistance or collateral susceptibility to other agents (Maeda and Furusawa, 2024). For instance, envelope remodeling selected by AMP exposure can influence susceptibility to certain cell-wall-active antibiotics, whereas antibiotic-driven regulatory changes may alter membrane properties relevant to AMP activity (Dawan et al., 2021; Wang X. et al., 2025). Such overlaps underscore that resistance phenotypes cannot be interpreted in isolation but must be situated within broader evolutionary networks of selection (Casier et al., 2025).

5 Conclusions

This comparative perspective indicates that resistance to conventional antibiotics and AMPs emerges from distinct but partially overlapping adaptive landscapes. Conventional antibiotics predominantly select for discrete, genetically encoded mechanisms that are stable, heritable, and often transmissible, whereas reduced susceptibility to AMPs more frequently reflects coordinated physiological and regulatory adaptations that remodel the bacterial envelope and may impose substantial fitness costs, resulting in more dynamic and potentially reversible phenotypes. Importantly, these strategies should be understood as a continuum rather than mutually exclusive categories. Evolutionary outcomes depend on pharmacodynamic properties, exposure heterogeneity, and ecological context, which together determine the balance between transient phenotypic plasticity and stable genetic fixation. Recognizing this continuum provides a more realistic framework for interpreting susceptibility profiles and anticipating resistance persistence.

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Footnotes

Edited by: Kamala-Kannan Seralathan, Jeonbuk National University Specialized Campus, Republic of Korea

Reviewed by: Ronan A. Murphy, Free University of Berlin, Germany