Molecular mechanisms of antibiotic resistance in Gram-positive and Gram-negative bacteria - a narrative review

Abstract

Antimicrobial resistance (AMR) represents one of the most pressing global public health challenges of the 21st century, driven by the widespread inappropriate use of antibiotics and the remarkable adaptive capacity of pathogenic bacteria This narrative review provides an integrated comparative analysis of AMR mechanisms across Gram-positive and Gram-negative bacteria, with particular emphasis on clinically significant ESKAPE pathogens. The four principal resistance mechanisms: enzymatic drug inactivation, reduced drug uptake, target site modification, and active efflux, are examined comparatively across both organism groups, with emphasis on how their molecular basis and clinical significance differ between them. Biofilm formation is further addressed as a resistance-amplifying strategy, with discussion of organism-specific differences in matrix composition between Gram-positive and Gram-negative pathogens. Current and emerging diagnostic approaches for AMR detection are reviewed in relation to their differential applicability across organism groups, followed by a discussion of pharmacokinetic/pharmacodynamic optimization as a resistance-prevention strategy. Finally, lariocidin, a structurally novel ribosome-targeting lasso peptide with broad-spectrum activity against both Gram-positive and Gram-negative multidrug-resistant pathogens, is presented as an emerging therapeutic scaffold that circumvents resistance mechanisms operating across both bacterial groups. Where relevant, illustrative examples from pediatric populations are discussed, highlighting how diagnostic challenges and empirical prescribing may compound the impact of resistance in this group. Addressing AMR requires coordinated global efforts that integrate surveillance, research, policy-making, and education to ensure the continued efficacy of antimicrobial treatments.