Bacterial vancomycin-resistant

Infections acquired from an external source are referred to as exogenous infections. These infections may occur as a result of human-to-human transmission, contact with exogenous bacterial populations in the environment, and animal contact. Resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus spp. 

Linezohd (Zyvox) is an oxazolidinone, a tive-membered heterocychc ring that forms the core of the hnezohd structure. The approval of hnezohd by the FDA in 2000 marked the first new structural class of antibacterial introduced into medical practice in the United States in 40 years. It is notable for its activity against methicillin-resistant Staph aureus, MRSA, and vancomycin-resistant Enterococcus faecium, VRE. It is bacteriostatic rather than bactericidal but finds significant use in patients with an intact immune system. Like several other classes of antibacterials, linezolid is an inhibitor of protein synthesis. It interacts specifically with the RNA component of a bacterial ribosome subunit to prevent initiation of protein synthesis. 

Aminomethyl- cyclines Amino- methyl- cycline MK-2764 (PTK-0796 BAY 73-7388) (153) Antibacterial (broad spectrum antibiotic against MRS A, MDR Streptococcus pneumoniae and vancomycin-resistant enterococci) Inhibits bacterial protein synthesis Phase III (treatment of hospital infections in both oral and i.v. injectable formulations) Paratek/Novartis 810... 

More recently, eveminomycins have also been introduced as antibiotics that inhibit the synthesis of bacterial cell walls. They show excellent activity against fluoroquinolone-resistant bacteria and all gram-positive vancomycin-resistant bacteria (Lin et al., 2000). 

Linezolid Prevents bacterial protein synthesis by binding to the 23S ribosomal RNA of 50S subunit Bacteriostatic activity against susceptible bacteria Infections caused by methicillin-resistant staphylococci and vancomycin-resistant enterococci Oral, IV hepatic clearance (half-life 6 h) dosed twice-daily Toxicity Duration-dependent bone marrow suppression, neuropathy, and optic neuritis serotonin-syndrome may occur when coadministered with other serotonergic drugs (eg, selective serotonin reuptake inhibitors)... 

Vancomycin inhibits bacterial cell wall synthesis and is bactericidal during cell division at therapeutic concentrations. Bacterial resistance to vancomycin has not been an issue during the first decades of its use. More recently, vancomycin-resistant enterococci have been recovered with increasing frequency from hospitalized patients. In some institutions, multidrug-resistant and vancomycin-resistant enterococci have become important nosocomial pathogens, difficult to treat. Vancomycin-resistant enter-ococcal bacteremia is associated with a poor prognosis. Judicious use of vancomycin and broad-spectrum antibiotics is recommended, and strict infection control measures must be implemented to prevent nosocomial transmission of these organisms (5). 

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. 

With the emergence of bacterial strains that are resistant to these glycopeptides, the first line of defense is often to synthetically modify the natural antibiotic. In the case of these glycopeptides, synthetic alteration of the aglycone stmcture is not practical, due to their complexity. However, the carbohydrate portion of the molecule [vancosamine(a l-2)glucose in the case of vancomycin] is readily accessible to modification. This strategy has led to new antibiotics that have potential for treatment of vancomycin-resistant strains. 

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. 

Two important new streptogramins are quinu-pristin (Fig. 10.15A) and dalfopristin (Fig. 10.15B), which are derivatives of pristinamycin I and IIA, respectively. Individually, the two components are bacteristatic but in combination they act synergistically to produce a bactericidal effect by inhibiting early (dalfopristin) and late (quinupristin) phases of bacterial protein synthesis. These two antibiotics are used intravenously in combination (ratio 30 70) for the treatment of serious or life-threatening infections associated with vancomycin-resistant Enterococcus faecium bacteraemia, although the effect against this organism is bacteristatic. 

The Gellman laboratories later reported the chemical synthesis of a 17-mer based on the 12-helix forming trani-2-aminocyclopentanoic acids [64]. Charged amine fimctionalities in combination with neutral monomer units were incorporated into the oligomer to provide an amphiphilic secondary structure (Fig. 35). When tested for bactericidal and bacteriostatic activity against a vancomycin-resistant bacterial strain, this material exhibited activity similar to that of a known 23-mer... 

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