Beta-lactam antibiotics resistance mechanisms

J. M. Frere, B. Joris, B. Granier, A. Matagne, F. Jacob, C. Bourguignon-Bellefroid, Diversity of the Mechanisms of Resistance to beta-Lactam Antibiotics , Res. Microbiol. 1991, 142, 705-710. 

Resistance of pathogenic microorganisms to beta-lactam antibiotics can result from one or a few of the mechanisms listed below inability of the drug to directly find an active site a change in PBP function, which is expressed in the reduction of affinity to the drag or inactivation of the drug by bacterial enzymes. 

Beta-lactam antibiotics must pass through the outer layer of the cell in order to get the desired PBP to the surface of the membrane. In Gram-positive bacteria, the cell membrane is the only layer covering the cytoplasmic membrane. In a few types of this bacteria, there is a polysaccharide capsule on the outer side of the cell membrane. However, not one of the described structures can serve as a barrier for the diffusion of small molecules such as beta-lactams. Therefore, the idea that the cause of possible resistance is the inability of beta-lactam antibiotics to get the desired PBP is not likely to be a possible mechanism of resistance for Gram-positive bacteria. 

The second mechanism of resistance to beta-lactam antibiotics can appear as a change in target PBP, which is expressed in a reduction in the affinity to beta-lactam molecules. 

Finally, the most important mechanism of resistance to beta-lactam antibiotics is the production of beta-lactamase by the bacteria. Beta-lactamases break the C-N bond in the beta-lactam ring of antibiotics. Since its existence is absolutely necessary for reacting with PBP, a break in the beta-lactam ring leads to a loss of antibacterial activity. 

The first completely synthetic monocyclic beta-lactam antibiotic was aztreonam. The antimicrobial activity of this drug is exhibited mainly with respect to a broad spectrum of aerobic Gram-negative bacteria. It is resistant to beta-lactamases and does not induce their formation. The mechanism of its action is identical to that of other beta-lactam antibiotics with respect to Gram-negative bacteria. PBP are inactivated in the presence of aztreonam. 

The glycopeptides include vancomycin and teico-planin. They are bactericidal antibiotics. Their mechanism of action is based on inhibition of bacterial cell-wall synthesis by blocking the polymerization of glycopeptides. They do not act from within the peptidoglycan layer, as the beta-lactam antibiotics do, but intracellularly. The indications are mainly restricted to the management of severe or resistant staphylococcal infections, especially those caused by coagulase negative staphylococcal species such as S. epidermidis. 

Sandanayaka VP, Prashad AS. Resistance to beta-lactam antibiotics structure and mechanism based design of beta-lactamase inhibitors. Curr Med Chem. 2002 9 1145-1165. 

Resistance is a problem with antibiotics. Explain the mechanisms of resistance for the beta-lactam antibiotics ... 

Resistance to beta-lactam antibiotics may occur through a number of mechanisms ... 

Beta-lactamases are genetically and strnctnraUy closely related to peniciUin-bmding proteins. Their prodnction by bacteria is a major mechanism of resistance to the action of beta-lactam antibiotics. Dmgs have therefore been developed that inhibit beta-lactamase, as a way of overcoming this resistance (SEDA-20,229). They are beta-lactam compounds with particularly high affinities for beta-lactamases (1,2), which therefore act as competitive inhibitors of beta-lactamases. Beta-lactamase inhibitors have no important antimicrobial activity and are only given in combination with an antimicrobial beta-lactam. 

Describe the mechanisms underlying the resistance of bacteria to beta-lactam antibiotics. 

C. Mechanisms of Action and Resistance Beta-lactam antibiotics are bactericidal drugs. They act to inhibit cell wall synthesis by the following steps (Figure 43 2) (1) binding of the drug to specific receptors (penicillin-binding proteins PBPs) located in the bacterial cytoplasmic membrane (2) inhibition of transpeptidase enzymes that act to cross-link linear peptido-glycan chains which form part of the cell wall and (3) activation of autolytic enzymes that cause lesions in the bacterial cell wall. 

Answer A- Microbial resistance to fluoroquinolones is increasing, and some strains of Streptococcus pneumoniae are now resistant to ciprofloxacin. The mechanism can involve changes in the structure of topoisomerase IV, one of the targets of fluoroquinolones, which inhibit nucleic acid synthesis. Pneumococcal resistance to penicillins is also increasing via changes in penicillin-binding proteins (PBPs). The other mechanisms listed underlie microbial resistance to other antibiotics as follows sulfonamides (choice B), macrolides (choice C), extended-spectrum penicillins (choice D), and beta-lactams (choice E). 

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