Resistance beta-lactam antibiotics

The unique feature of MRSA is based on the acquisition of a low-affinity penicillin-binding protein for beta-lactam antibiotic molecules (the penicillin-binding protein 2A), which allows the bacteria to carry on synthesis of its cell wall, whereas the other penicillin-binding proteins are already inactivated by the high concentration of methicillin or other beta-lactamase-resistant 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. 

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. 

Monobactams like aztreonam are monocyclic, as opposed to bicyclic, beta-lactam antibiotics. They are beta-lactamase-resistant. The monobactams are active against gram negative rods but lack activity against gram positive bacteria or against anaerobes. They are administered intravenously and they are rapidly excreted in the urine. 

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. 

D. M. Gilbert (2001). Making sense of eukaryotic DNA replication origins. Science 294 96-99. T. D. Gootz (1985). Determinants of bacterial resistance to beta-lactam antibiotics. Annu. Rep. Med. Chem. 20 137-144. 

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. 

Wilke MS, Lovering AL, Strynadka NC. Beta-lactam antibiotic resistance a current structural perspective. Curr Opin Microbiol. 2005 8 525-533. 

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 ... 

Sykes, R. B., and Mathews, M. (1976). The Beta-Lactamases of Gram-Negative Bacteria and Their Role in Resistance to Beta-Lactam Antibiotics. 

The overwhelming majority of semisynthetic beta-lactam antibiotics, the penicillins and cephalosporin, currently available to physicians trace their origins to the intense research effort devoted to this field several decades ago. The emergence of pathogens resistant to those antibiotics has led some laboratories to revisit this field. The modified cephalosporin ceftobiprole (220), a compound with a rather complex extended side chain, has shown activity in the clinic against some strains of multidrug resistant bacteria. The synthesis starts with the well-precedented acylation of the of the cephalosporin (215), available in several steps from the commercially available 7-acetoxy cephalosporanic acid, with the activated... 

Eisher JE, Meroueh SO, Mobashery S. Bacterial resistance to 36. beta-lactam antibiotics compelUng opportunism, compelling opportunity. Chem Rev. 2005 105 395-424. 

As beta-lactam antibiotics have a narrow absorption window lying in the upper part of the small intestine (actively absorbed by Pept 1), a GRDF can be more beneficial as it can minimize the appearance of these compounds in the colon and thus prevent any undesirable activities in the colon including the development of microorganism s resistance, which is an important pharmacodynamic aspect. ... 

In 10% of patients taking digoxin, there is inactivation of up to 40% of the drug before absorption, by intestinal Eubacterium lentum. This can be reversed by antibiotics (334,335). The lack of effects of some beta-lactam antibiotics on serum digoxin concentrations in one study (336) might have been due to the small sample size or resistance of the bacteria. 

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. 

Nakae, T., Nakajima, A., Ono, T., Saito, K., and Yoneyama, H. (1999) Resistance to beta-lactam antibiotics in Pseudomonas aeruginosa due to interplay between the MexAB-OprM efflux pump and beta-lactamase. Antimicrobial Agents and Chemotherapy, 43 (5), 1301-1303. 

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