β-Lactam Resistance in ESKAPE Pathogens Mediated Through Modifications in Penicillin-Binding Proteins: An Overview

Abstract

Bacteria acquire b-lactam resistance through a multitude of mechanisms among which production of b-lactamases (enzymes that hydrolyze b-lactams) is the most common, especially in Gram-negatives. Structural changes in the high-molecular-weight, essential penicillinbinding proteins (PBPs) are widespread in Gram-positives and increasingly reported in Gram-negatives. PBP-mediated resistance is largely achieved by accumulation of mutation(s) resulting in reduced binding affinities of b-lactams. Herein, we discuss PBP-mediated resistance among ESKAPE pathogens that cause diverse hospital-and community-acquired infections globally.

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“…Additionally, mutations in genes encoding proteins like PBP3 (encoded by ftsI) contribute to β-lactam resistance. Specific mutations in PBP3 have been associated with β-lactam resistance in clinical strains (Sethuvel et al, 2023).…”

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“…Ultimately, PBP-mediated resistance has been frequently highlighted in recent research, with most antimicrobials preferentially targeting one PBP with higher affinity, hence the antimicrobial combinations we have discussed having been constructed in order to inhibit more PBPs for utmost efficiency. The literature is scarce in describing the frequency of these structural changes' occurrence, as it most certainly may be a multifactorial characteristic, however researchers consistently report that these modifications greatly impact the efficacy rates of antimicrobials (Sethuvel et al, 2023). Another potential mechanism of resistance is considered to be mutations in the structures of siderophore receptors1or iron transporters.…”

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“…Alternative low-affinity target acquisition ( Fig 1 ). Penicillin-binding proteins (PBPs) are enzymes involved in cell wall synthesis and are required to maintain the integrity and structure of the bacterial cell [ 24 , 25 ]. They are the target of β-lactam antibiotics which bind to PBPs and prevent them from carrying out their function, leading to weakening of the cell wall and cell death.…”

“…aureus ) ( Fig 1 , Mechanism 7), through the acquisition of the MGE Staphylococcal Cassette Chromosome mec (SCC mec ). Accumulation of mutations in the genes encoding PBPs that reduce the β-lactam binding affinity is another commonly utilised mechanism in bacteria [ 24 ] ( Fig 1 , Mechanism 5). Acquisition of plasmid-encoded genes such as vanA , that encodes the vancomycin/teicoplanin A-type resistance protein, can lead to vancomycin resistance in the gram-positive ESKAPE pathogens.…”