Antimicrobial resistance in Klebsiella pneumoniae: identification of bacterial DNA adenine methyltransferase as a novel drug target from hypothetical proteins using subtractive genomics

Abstract

Klebsiella pneumoniae is a gram-negative bacterium that is known for causing infection in nosocomial settings. As reported by the World Health Organization, carbapenem-resistant Enterobacteriaceae, a category that includes K. pneumoniae, are classified as an urgent threat, and the greatest concern is that these bacterial pathogens may acquire genetic traits that make them resistant towards antibiotics. The last class of antibiotics, carbapenems, are not able to combat these bacterial pathogens, allowing them to clonally expand antibiotic-resistant strains. Most antibiotics target essential pathways of bacterial cells; however, these targets are no longer susceptible to antibiotics. Hence, in our study, we focused on a hypothetical protein in K. pneumoniae that contains a DNA methylation protein domain, suggesting a new potential site as a drug target. DNA methylation regulates the attenuation of bacterial virulence. We integrated computational-aided drug design by using a bioinformatics approach to perform subtractive genomics, virtual screening, and fingerprint similarity search. We identified a new potential drug, koenimbine, which could be a novel antibiotic.

Comparative Omics Analysis for Novel Target Discovery in Plant Pathogens: A Case Study for Magnaporthe oryzae

“…S2). These results strongly suggest that G5K serves as a novel and promising broad-spectrum target for M. oryzae, being conserved across over 40 different pathogens (Mondal et al, 2015;Hossain et al, 2017;Cesur et al, 2020;Omeershffudin and Kumar, 2023).…”

Antibiotic resistance in Neisseria gonorrhoeae: broad-spectrum drug target identification using subtractive genomics

“…The subcellular localization was identified using PsortB 3.0 [ 37 ]. Proteins localized in the cytoplasm are viable drug targets, while membrane proteins are often targeted as vaccine candidates [ 12 ]. Membrane proteins are likely to secrete antigenic proteins that the immune system can detect, which is why they are preferred as potential vaccine candidates [ 38 ].…”

“…Target alteration or reduction of target affinity is one of the critical resistance mechanisms in N. gonorrhoeae. In a recent study, the bacteria were found to develop resistance against extended-spectrum cephalosporin, cefixime, and ceftriaxone [8][9][10][11]. Cefixime is also no longer recommended as a first-line regimen [1].…”

“…Thus, ever-growing efforts in the current biomedical arena utilize computational-aided drug design or in silico analysis to accelerate drug design and development [8]. Many studies have successfully identified potential drug targets and vaccine candidates using in silico methods [9][10][11][13][14][15][16][17].…”

“…Traditional drug development campaigns typically produce and test a few thousand compounds yearly, whereas computational technologies can accurately evaluate billions of molecules per week [ 12 ]. Thus, ever-growing efforts in the current biomedical arena utilize computational-aided drug design or in silico analysis to accelerate drug design and development [ 8 ].…”