Changing Landscape of Antimicrobial Resistance in Neonatal Sepsis: An in silico Analyses of Multidrug Resistance in Klebsiella pneumoniae.

Abstract

Neonatal sepsis poses a critical healthcare concern, as multidrug-resistant Klebsiella pneumoniae (K. pneumoniae) infections are on the rise. Understanding the antimicrobial susceptibility patterns and underlying resistance mechanism is crucial for effective treatment. This study aimed to comprehensively investigate the antimicrobial susceptibility patterns of K. pneumoniae strains responsible for neonatal sepsis using in silico tools. We sought to identify trends and explore reasons for varying resistance levels, particularly for β-lactams and fluoroquinolone. K. pneumoniae isolated from neonates at Kanchi Kamakoti CHILDS Trust Hospital (2017-2020) were analyzed for antimicrobial resistance. Elevated resistance to β-lactam and fluoroquinolone antibiotics was further investigated through molecular docking and interaction analysis. β-lactam affinity with penicillin-binding proteins and β-lactamases was examined. Mutations in ParC and GyrA responsible for quinolone resistance were introduced to investigate ciprofloxacin interactions. Of 111 K. pneumoniae blood sepsis isolates in neonates, high resistance was detected to β-lactams such as cefixime (85.91%, n = 71), ceftriaxone (84.9%, n = 106), cefotaxime (84.9%, n = 82) and fluoroquinolone (ciprofloxacin- 79.44%, n = 107). Molecular docking revealed low β-lactam binding toward penicillin-binding proteins and higher affinities for β-lactamases, attributing to the reduced β-lactam efficiency. Additionally, ciprofloxacin showed decreased affinity toward mutant ParC and GyrA in comparison to their corresponding wild-type proteins. Our study elucidates altered resistance profiles in neonatal sepsis caused by K. pneumoniae, highlighting mechanisms of β-lactam and fluoroquinolone resistance. It underscores the urgent need for the development of sustainable therapeutic alternatives to address the rising antimicrobial resistance in neonatal sepsis.