Abstract
BACKGROUND: AmpC β-lactamases (blaAmpC) are essential drivers of antimicrobial resistance (AMR) in ESKAPE pathogens, bacteria that cause hospital-acquired infections. Understanding AmpC enzymes is essential for uncovering resistance mechanisms and guiding antimicrobial strategies. We analyzed blaAmpC presence, genomic location, copy number, sequence variability, and evolutionary traits in ESKAPE pathogens. RESULTS: We identified 1790 AmpC enzymes in 4713 complete genomes, classified into nine enzyme groups. Consistent with known taxonomic profiles, no class C β-lactamases were detected in Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecium). Acinetobacter baumannii exhibited the highest occurrence of class C β-lactamases, with Enterobacter spp. showing the second highest prevalence, followed by Pseudomonas aeruginosa and Klebsiella pneumoniae. The largest enzyme group, ADC was restricted to A. baumannii; similarly, ACC, ACT, CMH, and MIR to Enterobacter spp.; and PDC and PIB to P. aeruginosa. Phylogenetic analysis showed divergence among some groups and closer evolutionary relationships in others. Functional Motif analysis revealed conserved catalytic residues across all groups except PIB. Instead of the canonical YXN and KTG motifs, PIB contains YST and AQG variants, respectively. Because of these variations, PIB's ability to bind cephalosporins decreases while enhancing their activity against carbapenems. CONCLUSIONS: We identified 1790 AmpC enzymes in nine distinct groups across ESKAPE pathogens, with species-specific distribution patterns and notable absence in Gram-positive bacteria. The PIB enzyme group demonstrated unique motif variants (YST/AQG) conferring carbapenem resistance, while other groups maintained conserved catalytic motifs. Phylogenetic analysis revealed evolutionary divergence and horizontal gene transfer potential, emphasizing the need for targeted therapeutic approaches against AmpC-mediated resistance.