Vancomycin bacterial resistance mechanisms

Daptomycin binds to bacterial membranes resulting in depolarization, loss of membrane potential, and cell death. It has concentration-dependent bactericidal activity. Due to its unique mechanism of action, cross-resistance with other antibiotic classes seems not to occur, and there are no known resistance mechanisms. There were two cases (one S. aureus and the other E. faecalis) among more than 1000 cases treated in which resistance emerged during therapy. Staphylococci with decreased susceptibility to vancomycin have higher daptomycin MICs than fully susceptible strains. 

An intervening chapter delineates the enzymatic basis for the bacterial resistance to five classes of antibiotics the /3-lactams (e.g., penicillin), the glycopeptides (e.g., vancomycin), the aminoglycosides (e.g., streptomycin), the macrolides (e.g., erythromycin), and the quinolones (e.g., ciprofloxacin). The classes represent the major antibiotics used clinically today. Starting with the /3-lactams and ending with the fluoroquinolones, the authors discuss the mechanisms and molecular basis for resistance, and show how resistance is not a matter of if, but when. 

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. 

Vancomycin is most often the antibiotic of last resort for the treatment of resistant bacterial strains, however, bacterial strains resistant to vancomycin are now emerging [19]. The health threat posed by these strains has led to intense research into both the mechanism by which resistance develops and the development of pharmaceutical antibacterial agents with novel modes of action. 

It has been observed that the incorporation of lipophilic chains into vancomycin can increase the potency of the dmg [159,160,161,162]. This is best exemplified by the observation that teicoplanin retains activity against some vancomycin-resistant bacterial strains. In one early study directed at improving the efficacy of these antibiotics, Ge et al. investigated the mechanism of action of a chloro-biphenyl derivative of vancomycin that showed activity against resistant bacteria [163]. The sulfoxide method of glycosylation was utilized to achieve the desired modification of the gluco-vancomycin precursor (O Scheme 28). 

Ramoplanin is a lipoglycodepsipeptide isolated from a fermentation broth of Actinoplanes which showed potent antibiotic activity against a number of vancomycin resistant bacterial strains [178]. This compound is currently undergoing phase m clinical trials. While the mechanism of action of ramoplanin remains to be elucidated, it appears that the glycans are not necessary for biological activity and their function remains to be established. 

Vancomycin and other glycopeptide antibiotics exert their antibacterial effect by inhibition of the synthesis of pcptidoglycan, the principal component of the bacterial cell wall. The mechanism of action has been extensively studied, and excellent reviews of both the biochemical and molecular bases of action are available (39,40). Still, new insights continue to develop, especially now that resistance has emerged (41). 

Abstract Medical studies established that vancomycin and other related macro-cyclic antibiotics have an enhanced antimicrobial activity when they are associated as dimers. The carbohydrate units attached to the vancomycin basket have an essential role in the dimerization reaction. Covalently synthesized dimers were found active against vancomycin-resistant bacterial strains. A great similarity between antibiotic potential and enantioselectivity was established. A covalent vancomycin dimer was studied in capillary electrophoresis producing excellent chiral separation of dansyl amino acids. Balhimycin is a macrocyclic glycopeptide stmcturally similar to vancomycin. The small differences are, however, responsible for drastic differences in enantioselectivity in the same experimental conditions. Contributions from studies examining vancomycin s mechanism for antimicrobial activity have substantially aided our understanding of its mechanism in chiral recognition. 

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