Karthik Maruthan, Kacha Srujal, Rajendran Subbulakshmi, Bakthavatchalam Yamuna Devi, Lal Binesh, Walia Kamini, Veeraraghavan Balaji
Department of Clinical Microbiology, Christian Medical College, Vellore 632004, India.
Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research, New Delhi, India.
Infect Genet Evol. 2024 Dec;126:105701. doi: 10.1016/j.meegid.2024.105701. Epub 2024 Dec 7.
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.
铜绿假单胞菌表现出显著的抗生素耐药性，这是由内在和获得性机制促成的，主要是通过铜绿假单胞菌衍生的头孢菌素酶（PDC），即由AmpC编码的丝氨酸安布勒C类β-内酰胺酶。AmpC参与肽聚糖循环途径，受ampD、ampR和ampG等基因调控，导致对各种β-内酰胺类药物的表达增加和耐药性增强。PDC分为三种主要类型：经典C类β-内酰胺酶、超广谱C类β-内酰胺酶（ESACβ-内酰胺酶）和抑制剂耐药C类β-内酰胺酶。本研究旨在确定印度和全球铜绿假单胞菌分离株中普遍存在的PDC变体及其遗传特征，重点关注它们在β-内酰胺耐药性中的作用。通过分析在韦洛尔基督教医学院（CMC）收集的111株铜绿假单胞菌分离株的PDC序列，我们发现ESAC等位基因PDC-447在印度分离株中最为普遍，存在于18%的碳青霉烯耐药菌株和11%的碳青霉烯敏感菌株中。使用NCBI PathogenWatch数据库对全球和印度分离株的PDC变体进行了验证，并将测序的PDC区域与PDC-1进行了比较。PDC-398和PDC-397在碳青霉烯耐药分离株中的流行率次之，而PDC-5（ESAC）和PDC-1（经典C类）在碳青霉烯敏感菌株中较为常见。对19478个基因组的全球分析显示，ESAC变体如PDC-3（17.28%）和PDC-5（12.91%）以及经典C类β-内酰胺酶如PDC-8（10.65%）的流行率很高。印度分离株表现出不同的模式，PDC-3和PDC-5的流行率分别为19.84%和10%。PDC的ω环、H螺旋和R2区域的突变与抗生素耐药性增强有关，特别是H螺旋区域的T105A突变。这些发现强调了铜绿假单胞菌抗菌耐药机制的复杂性，并突出了需要新的治疗策略和持续监测来管理这种多面病原体引起的感染。了解PDC变体的流行率和遗传特征对于针对铜绿假单胞菌的有效治疗策略和对抗抗生素耐药性至关重要。
