The widespread appearance of methicillin resistant Staphylococcus aureus (MRSA) has significantly undermined the efficacy of currently available antibiotic therapies as strains tend to be multi-resistant. Clinicians are therefore faced with a restricted choice in effective anti-MRSA therapies for infection or elimination of carriage. MRSA remain uniformly susceptible to glycopeptides vancomycin and teicoplanin which remain drugs of choice in treatment of infections. Centres with a high incidence of MRSA should use glycopeptides as empirical monotherapies against these organisms. The low toxicity of teicoplanin makes it an alternative for patients unable to tolerate vancomycin. Only mupirocin is truly effective for use as a topical agent in elimination of MRSA colonisation. For systemic use developmental glycopeptides such as daptomycin, MDL 63246, and LY191145 show better in vitro activity than vancomycin. New cephalosporins TOC-39 and FK-037 show promising anti-MRSA potential with low MICs, as does carbapenem BO-2727 which has a high in vitro activity. Whether the new cephalosporins and carbapenems with good in vitro and/or in vivo activities against MRSA will be clinically effective remains to be determined. New fluoroquinolones levofloxacin, temafloxacin and sparfloxacin have enhanced in vitro anti-MRSA activity, although the emergence of resistance, and subsequent cross resistance to related compounds during therapy is a problem. BAY 12-8039, DV-7751 and CS-940 are developmental fluoroquinolones with better in vitro activity and lower spontaneous mutation rates than related compounds. Co-trimoxazole shows good in vivo anti-MRSA activity, comparable to vancomycin, however, severe infections do not respond well and many strains are resistant to this drug. Rifampicin has excellent bactericidal activity but rapidly emerging resistance undermines its use as a monotherapy. Its use in a combination therapy offers limited potential as an alternative. Arbekacin shows good in vitro activity against many MRSA isolates, although resistance to related aminoglycosides is a problem. Streptogramins, virginiamicin and RP 59500 (dalfopristin/quinupristin), and the everninomicin SCH 27899, show excellent activity in vitro and in vivo activity against MRSA and real future potential as alternative agents to vancomycin. Azeleic acid and ramoplanin show future potential as agents for topical use against MRSA. In conclusion only vancomycin as a systemic agent and mupirocin as a topical agent, offer sufficient reliability for use against MSRA. Alternatives to glycopeptides and mupirocin rest with the development of new drugs from several classes of compounds.

01 Jan 1997·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Molecular interactions of a semisynthetic glycopeptide antibiotic with D-alanyl-D-alanine and D-alanyl-D-lactate residues

Q2 · MEDICINE

Article

Author: Allen, N E ; LeTourneau, D L ; Hobbs, J N

LY191145 is an N-alkylated glycopeptide antibiotic (the p-chlorobenzyl derivative of LY264826) with activity against vancomycin-susceptible and -resistant bacteria. Similar to vancomycin, LY191145 inhibited polymerization of peptidoglycan when muramyl pentapeptide served as a substrate but not when muramyl tetrapeptide was used, signifying a substrate-dependent mechanism of inhibition. Examination of ligand binding affinities for LY191145 and the effects of this agent on R39 D,D-carboxypeptidase action showed that, similar to vancomycin, LY191145 had an 800-fold greater affinity for N,N'-diacetyl-L-Lys-D-Ala-D-Ala than for N,N'-diacetyl-L-Lys-D-Ala-D-Lac. The antibacterial activity of LY191145 was antagonized by N,N'-diacetyl-L-Lys-D-Ala-D-Ala, but the molar excess required for complete suppression exceeded that needed to suppress inhibition by vancomycin. LY191145 is strongly dimerized and the p-chlorobenzyl side chain facilitates interactions with bacterial membranes. These findings are consistent with a mechanism of inhibition where interactions between antibiotic and D-Ala-D-Ala or D-Ala-D-Lac residues depend on intramolecular effects occurring at the subcellular target site.

01 Oct 1996·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Inhibition of peptidoglycan biosynthesis in vancomycin-susceptible and -resistant bacteria by a semisynthetic glycopeptide antibiotic

Q2 · MEDICINE

Article

Author: Hobbs, J N ; Allen, N E ; Nicas, T I

LY191145 is a p-chlorobenzyl derivative of LY264826 (A82846B) with activity against both vancomycin-susceptible and -resistant enterococci. Incorporation of L-[14C]lysine into peptidoglycan of intact vancomycin-susceptible and -resistant Enterococcus faecium was inhibited by LY191145 (50% inhibitory concentrations of 1 and 5 microgram/ml, respectively). Inhibition was accompanied by accumulation of UDP-muramyl-peptide precursors in the cytoplasm. This agent inhibited late-stage steps in peptidoglycan biosynthesis in permeabilized E. faecium when either the UDP-muramyl-pentapeptide precursor from vancomycin-susceptible E. faecium or the UDP-muramyl-pentadepsipeptide precursor from vancomycin-resistant E. faecium was used as a substrate. Inhibition of late-stage steps led to accumulation of an N-acetyl-[14C]glucosamine-labeled lipid intermediate indicative of inhibition of the transglycosylation step. Inhibition of peptidoglycan polymerization without affecting cross-linking in a particulate membrane-plus-wall-fragment assay from Aerococcus viridans was consistent with this explanation. The fact that inhibition of peptidoglycan biosynthesis by LY191145 was not readily antagonized by an excess of free acyl-D-alanyl-D-alanine or acyl-D-alanyl-D-lactate ligands indicates that the manner in which this compound inhibits transglycosylation may not be identical to that of vancomycin.

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Indication	Highest Phase	Country/Location	Organization	Date
Staphylococcal Infections	Discovery	United States	Lilly Research Laboratories	01 Nov 1995

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