Abstract
The consistently mutating bacterial genotypes appear to have accelerated the global challenge with antimicrobial resistance (AMR); it is therefore timely to investigate certain less-explored fields of targeting AMR mechanisms in bacterial pathogens. One of such areas is beta-lactamase (BLA) induction that can provide us with a collection of prospective therapeutic targets. The key genes (ampD, ampE and ampG) to which the AmpC induction mechanism is linked are also involved in regulating the production of fragmented muropeptides generated during cell-wall peptidoglycan recycling. Although the involvement of these genes in inducing class C BLAs is apparent, their effect on serine beta-lactamase (serine-BLA) induction is little known. Here, by using ∆ampD and ∆ampE mutants of E. coli, we attempted to elucidate the effects of ampD and ampE on the expression of serine-BLAs originating from Enterobacteriaceae, viz., CTX-M-15, TEM-1 and OXA-2. Results show that cefotaxime is the preferred inducer for CTX-M-15 and amoxicillin for TEM-1, whereas oxacillin for OXA-2. Surprisingly, exogenous BLA expressions are elevated in ∆ampD and ∆ampE mutants but do not always alter their beta-lactam susceptibility. Moreover, the beta-lactam resistance is increased upon in trans expression of ampD, whereas the same is decreased upon ampE expression, indicating a differential effect of ampD and ampE overexpression. In a nutshell, depending on the BLA, AmpD amidase moderately facilitates a varying level of serine-BLA expression whereas AmpE transporter acts likely as a negative regulator of serine-BLA.
Highlights
The unique features of the bacterial cell wall make it a promising target for the majority of antimicrobial agents [1,2]
The biosynthesis and recycling of cell-wall PG involve multiple enzymatic steps in various locations of the bacterial cells, which are widely investigated for developing antimicrobial agents [1,2,4,5]
The enzymatic steps in cross-link formation are catalyzed by a set of ectoproteins present in the periplasm known as penicillin-binding proteins (PBPs) [8,9]
Summary
The unique features of the bacterial cell wall make it a promising target for the majority of antimicrobial agents [1,2]. The biosynthesis and recycling of cell-wall PG involve multiple enzymatic steps in various locations of the bacterial cells, which are widely investigated for developing antimicrobial agents [1,2,4,5]. The enzymatic steps in cross-link formation are catalyzed by a set of ectoproteins (tethered at the outer facet of cytoplasmic membrane) present in the periplasm known as penicillin-binding proteins (PBPs) [8,9]. The constant evolution of beta-lactam hydrolyzing enzymes, beta-lactamases (BLA), is limiting their use in clinical settings. These BLAs are broadly classified into four classes (A–D) by Ambler et al [11]. The enzymes from classes A, C and D require an active-site serine residue for their activity whereas class B are metallo-BLAs that require zinc ions to exert their effect on beta-lactams [11]
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