AmpC β-lactamases: A Key to Antibiotic Resistance in ESKAPE Pathogens

Abstract

AmpC {beta}-lactamases (blaAmpC) are one of the important drivers for a high incidence of antimicrobial resistance (AMR) within ESKAPE pathogens, which are a group of bacteria that are the leading cause of hospital-acquired infections. Investigating the presence and characteristics of the blaAmpC is essential for understanding the molecular mechanism of resistance and developing effective strategies to combat AMR. We have investigated the presence of blaAmpC, distribution on plasmids/chromosomes, copy number, amino acid identities/variabilities, and evolutionary characteristics in ESKAPE pathogens. Our analysis indicates 1790 AmpC enzymes in 4713 completely assembled genomes, subdivided into nine different enzyme groups. AmpC is more common in A. baumannii, followed by P. aeruginosa, K. pneumoniae, and Enterobacter spp., but absent in E. faecium and S. aureus. Among the nine AmpC enzyme groups, ACC, ACT, CMH, and MIR are exclusively found in Enterobacter spp., while the largest enzyme group ADC is only present in A. baumannii; PDC and PIB are found only in P. aeruginosa. Phylogenetic analysis revealed significant divergence amongst few enzyme groups and closer evolutionary relationships within others. Functional motif analysis identified conserved catalytic residues across all enzyme groups, except PIB, which demonstrates structural and functional divergence. Because of these variations, PIBs ability to bind cephalosporins decreases while enhancing its activity against carbapenems, hence, we have excluded PIB from further analysis. This is the first detailed report on AmpC in ESKAPE pathogens, which also re-emphasizes the wise use of antibiotics to reduce the rise of AmpC cephalosporins resistance, a significant public health concern. HighlightsO_LIFirst detailed report on ESKAPE blaAmpC localization in chromosomes and plasmids C_LIO_LIblaAmpC is absent in E. faecium & S. aureus but prevalent in other four pathogens C_LIO_LIMost blaAmpC belong to ADC, exclusively present in A. baumannii chromosomes C_LIO_LIInterspecies gene exchange in K. pneumoniae, P. aeruginosa & Enterobacter spp. C_LIO_LIEvolutionary analysis shows recent divergence & possible horizontal gene transfer C_LI