Genetic characteristics and diversity of PDC variants of Pseudomonas aeruginosa and its clinical relevance

Pseudomonas aeruginosa exhibits significant antibiotic resistance facilitated by both intrinsic and acquired mechanisms, prominently through Pseudomonas-derived cephalosporinase (PDC), serine Ambler class C β-lactamases encoded by the AmpC. AmpC, involved in the peptidoglycan recycling pathway, is regulated by genes such as ampD, ampR, and ampG, leading to increased expression and resistance to various beta-lactams. PDCs are classified into three main types: classical class C β-lactamases, extended-spectrum class C β-lactamases (ESAC β-lactamases), and inhibitor-resistant class C β-lactamases. This study aimed to identify prevalent PDC variants and its genetic characteristics in Indian and global P. aeruginosa isolates, focusing on their role in β-lactam resistance. Analyzing PDC sequences from 111 P. aeruginosa isolates collected at Christian Medical College (CMC), Vellore, we found the ESAC allele PDC-447 to be the most widespread among Indian isolates, present in 18 % of carbapenem-resistant and 11 % of carbapenem-susceptible strains. Global and Indian isolates PDC variants were validated using the NCBI PathogenWatch database, and the sequenced PDC region compared to PDC-1. PDC-398 and PDC-397 followed in prevalence among carbapenem-resistant isolates, while PDC-5 (ESAC) and PDC-1 (classical class C) were common in carbapenem-susceptible strains. A global analysis of 19,478 genomes revealed significant prevalence of ESAC variants such as PDC-3 (17.28 %) and PDC-5 (12.91 %), alongside classical class C beta-lactamases like PDC-8 (10.65 %). Indian isolates exhibited distinct patterns with PDC-3 and PDC-5 prevailing at 19.84 % and 10 %, respectively. Mutations in the omega loop, H-helix, and R2 region of PDCs were linked to enhanced antibiotic resistance, particularly the T105A mutation in the H-helix region. These findings underscore the complexity of antimicrobial resistance mechanisms in P. aeruginosa and highlight the need for novel therapeutic strategies and continuous surveillance to manage infections by this versatile pathogen. Understanding the prevalence and genetic characteristics of PDC variants is crucial for effective treatment strategies against P. aeruginosa and combating antibiotic resistance.