Antimicrobial peptides (AMPs) are crucial components of innate immunity and promising leads for new anti-infective therapies, prized for their broad-spectrum activity and membrane-disruptive mechanisms. However, traditional models of antimicrobial action and resistance often focus on single-cell responses or genetically encoded resistance, overlooking the complex collective behaviors of bacteria at the population level. A growing body of evidence indicates that bacterial communities can profoundly influence AMP efficacy through emergent, community-level resistance mechanisms. In this review, we examine how population-level dynamics and interactions enable bacteria to withstand AMPs beyond what is predicted by cell-autonomous models. We first describe the mechanisms of peptide sequestration by bacterial debris, dead cells, outer membrane vesicles, and biofilm matrix polymers, which diminish the concentration of active peptide available to kill neighboring cells. We then analyze how population-level traits—including inoculum effects, phenotypic heterogeneity, and persister subpopulations—shape survival outcomes and promote regrowth after treatment. Cooperative processes such as protease secretion further enhance communal defenses by coordinating or amplifying protective responses. Beyond cataloging these mechanisms, we highlight recent advances in microfluidic tools, single-cell imaging, and biophysical modeling that reveal the spatial and temporal dynamics of AMP action in structured populations. Collectively, these insights show how bacterial communities absorb, neutralize, or delay AMP activity without genetic resistance, with important implications for therapeutic design and the evaluation of AMP efficacy.
Mekdessi et al. (Mon,) studied this question.