Mechanisms of Action of Carbapenem Resistance

Abstract

Carbapenem antibiotics are the most effective antimicrobials for the treatment of infections caused by the most resistant bacteria. They belong to the category of β-lactams that include the penicillins, cephalosporins, monobactams and carbapenems. This class of antimicrobials has a broader spectrum of activity than most other beta-lactams antibiotics and are the most effective against Gram-positive and Gram-negative bacteria. All β-lactams antibiotics have a similar molecular structure: the carbapenems together with the β-lactams. This combination gives an extraordinary stability to the molecule against the enzymes inactivating the β-lactams. They are safe to use and therefore widespread use in many countries has given rise to carbapenem resistance which is a major global public health problem. The carbapenem resistance in some species is intrinsic and consists of the capacity to resist the action of antibiotics with several mechanisms: for the absence of a specific target, or an intrinsic difference in the composition of cytoplasmatic membrane or the inability to cross the outer membrane. In addition to intrinsic resistance, bacteria can develop resistance to antibiotics with several mechanisms that can be gathered in three main groups. The first group includes antibiotics with poor penetration into the outer membrane of bacterium or antibiotic efflux. The second includes bacteria that modify the target of the antibiotics through genetic mutations or post-translational modification of the target. The third includes bacteria that act with enzyme-catalyzed modification and this is due to the production of beta-lactamases, that are able to inactivate carbapenems and so called carbapenemases. In this review, we focus on the mode of action of carbapenem and the mechanisms of carbapenem resistance.

Antimicrobial resistance among GLASS pathogens in Morocco: an epidemiological scoping review

“…It bind to the bacterial cell wall and inhibits growth. It also results in damage to the cell wall, which frequently leads to cell lysis and death [ 13 , 72 , 73 ]. Carbapenem resistance may be caused by different mechanisms, one of them being inducible overexpression of chromosomal cephalosporinases combined with porin loss [ 74 , 75 ].…”

Identification and characterization of a novel metallo β-lactamase, SZM-1, in Shenzhen Bay, South China

“…Carbapenem is one of the last-resort β-lactam antibiotics for the treatment of serious bacterial infections that caused by gram-negative bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumonia. Nevertheless, multiple molecular mechanisms that confer bacterial resistance phenotype become the major Fang et al 10.3389/fmicb.2022.996834 barrier to the clinical application of the drug (Kelly et al, 2017;Aurilio et al, 2022). As one of such mechanisms, metalloβ-lactamases (MBLs), can directly degrade β-lactam ring of the carbapenem and most other β-lactam antibiotics, through their zinc dependent catalytic active center (Abbas, 2021).…”

The l,d-Transpeptidase LdtAb from Acinetobacter baumannii Is Poorly Inhibited by Carbapenems and Has a Unique Structural Architecture

“…However, over time, bacteria have developed and utilized various defensive mechanisms, allowing them to withstand the deleterious effects of β-lactam antibiotics. These mechanisms include production of β-lactam-degrading enzymes, β-lactamases, mutational alterations of their targets, DDTs, mutations hindering penetration of the drugs through the outer membrane of Gram-negative bacteria, and activation of efflux pumps transporting antibiotics from the cell back to the milieu . It was demonstrated that LDTs also can contribute to bacterial resistance to β-lactams, as they are not efficiently inhibited by the majority of these drugs, with the exception of carbapenems. ,,,− Consequently, this allows bacterial pathogens to survive in the presence of many β-lactams, as they can maintain the integrity of their cell wall by increasing formation of 3–3 cross-linked peptidoglycan, to compensate for the decrease of 4–3 cross-linked species resulting from inhibition of DDTs. , …”