OXA-23 β-Lactamase Overexpression in Acinetobacter baumannii Drives Physiological Changes Resulting in New Genetic Vulnerabilities

Abstract

Acinetobacter baumannii has become a serious pathogen in both hospital and community settings. The β-lactam class of antibiotics is a primary treatment option for A. baumannii infections, and expression of β-lactamases is the most frequent mechanism of resistance in this bacterium.

Role of Enzymatic Activity in the Biological Cost Associated with the Production of AmpC β-Lactamases in Pseudomonas aeruginosa

“…Within the field of the interplay between resistance and fitness/virulence, during the last years, several studies on the balance between the expression of acquired β-lactamases and the associated biological costs were reported, providing a notable variety of results ranging from no significant cost ( 8 – 13 , 25 ) to almost unbearable burdens, as happens in Salmonella enterica ( 8 , 12 , 13 , 18 – 20 , 25 ). The mechanisms causing these potentially associated biological costs are diverse, including issues related to growth defects, adherence, biofilm formation, and alterations in the peptidoglycan, etc.…”

“…Moreover, the widespread dissemination of several transferable β-lactamases (including extended-spectrum β-lactamases [ESBLs] and carbapenemases) in certain Gram-negative bacteria strongly suggests that their carriage does not represent a significant handicap for fitness/virulence or at least that under antibiotic pressure, many enzymes are positively selected as they provide more advantages than drawbacks for bacteria ( 14 – 17 ). Conversely, other studies show that depending on the species and enzyme considered, the associated biological burden is very important, although the basis for this output is mechanistically variable ( 8 , 12 , 13 , 18 – 20 ). Meanwhile, the topic of the biological cost potentially associated with the mutation-mediated hyperproduction of intrinsic β-lactamases has barely been addressed in Gram-negative bacteria ( 8 ).…”

Costs of antibiotic resistance genes depend on host strain and environment and can influence community composition

“…β-lactamases also have similarity with the penicillin binding proteins (PBPs) that process peptidoglycan components of cell walls. Residual activity of β-lactamases for PBP substrates might interfere with the dynamic process of peptidoglycan processing required to accommodate cell growth (21, 22). The host strains we used are genetically distinct, likely leading to different metabolic, physiological, and regulatory backgrounds on which effects of ARGs are tested.…”

“…The benefit conferred by ARGs to host cells during antibiotic exposure is, however, only one factor determining their overall success [8][9][10][11]. Of 22 ARGs for which a recent origin could be inferred, most were from species with human or domestic animal association [5]. This association is linked to antibiotic exposure, supporting the idea that direct selection for resistance is important for the success of ARGs [12].…”

“…Studies estimating the effect of specific ARGs include analysis of the tetAR operon, encoding tetracycline resistance, that was estimated to impose a cost of around 1% in rich medium [18,19]. Similarly, βlactamases, a large class of resistance genes that confer resistance to one or more of the β-lactam antibiotics, have been shown to decrease host fitness, though different variants have different effects in different hosts [20][21][22][23]. In at least some cases, however, ARGs, including tetAR, not only do not confer a cost but can provide a benefit to host cells, underlining the importance of understanding potential variation in costs across different hosts [24][25][26].…”