New therapeutic agents for resistant Gram-positive infections

Ziglam, Hisham; Nathwani, D.

doi:10.1586/14787210.1.4.655

Cited by 3 publications

(3 citation statements)

References 33 publications

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“…The ongoing search for new antistaphylococcal agents (1,6,30,48) is justified by the continuing increase in nosocomial MRSA isolates displaying multidrug resistance and by the recent appearance and dissemination of distinct clones of community acquired MRSA (8,31). While some recently approved antimicrobials circumvent mechanisms conferring methicillin resistance (17), ceftobiprole directly targets PBP2Ј, whose low affinity for marketed ␤-lactams is responsible for the methicillin resistance phenotype (22).…”

Section: Discussionmentioning

confidence: 99%

Intensive Therapy with Ceftobiprole Medocaril of Experimental Foreign-Body Infection by Methicillin-Resistant Staphylococcus aureus

Vaudaux

Gjinovci

Bento

et al. 2005

Antimicrob Agents Chemother

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The therapeutic activity of ceftobiprole medocaril, the water-soluble prodrug of ceftobiprole, was compared to that of vancomycin in a rat tissue cage model of chronic methicillin-resistant Staphylococcus aureus (MRSA) foreign-body infection. The MICs and MBCs of ceftobiprole and vancomycin in Mueller-Hinton broth for strain MRGR3 were 1 and 4 and 1 and 2 g/ml, respectively. In vitro elimination rates of strain MRGR3 of 4 and 8 g/ml of ceftobiprole or vancomycin were equivalent. After 2 weeks of infection, mean ؎ standard error of the mean viable counts of strain MRGR3 were 6.83 ؎ 0.11 log CFU/ml of tissue cage fluid (n ‫؍‬ 87). High-dose regimens of ceftobiprole medocaril (equivalent to 150 mg/kg of ceftobiprole) or 50 mg/kg vancomycin produced nearly identical average peak and trough levels of ceftobiprole and vancomycin in tissue cage fluid, which exceeded the MBC of either antibiotic towards strain MRGR3 for >75% of each dosing interval. After 7 days of therapy with ceftobiprole medocaril or vancomycin, average counts of MRGR3 decreased significantly (P < 0.02) by 0.68 ؎ 0.28 (n ‫؍‬ 29) and 0.88 ؎ 0.22 (n ‫؍‬ 28) log CFU/ml of tissue cage fluid, respectively, compared with cages of untreated animals, but were not significantly different from each other. No resistant mutants were detected on ceftobiprole-supplemented agar following therapy with this cephalosporin. The in vivo activity of ceftobiprole medocaril against chronic MRSA foreign-body infections was equivalent to that of vancomycin and did not lead to the emergence of resistant subpopulations.Infections due to Staphylococcus aureus associated with foreign implants, such as orthopedic prostheses and permanently inserted catheters, are very difficult to manage by antimicrobial chemotherapy. Semisynthetic penicillins, imipenem, vancomycin, fluoroquinolones, and glycopeptides show limited or no significant efficacy in the clinic or experimental therapy of prosthetic infections, and treatment with these drugs for this indication often result in clinical failures (4, 45). The increasing prevalence of clinical isolates of methicillin-resistant S. aureus (MRSA), which frequently display multidrug resistance against all semisynthetic penicillins, penems, macrolides, aminoglycosides, and fluoroquinolones, is a worldwide problem (8,16,31). Multidrug-resistant S. aureus is of particular concern because of its widespread occurrence, intrinsic virulence, and high adaptability to diverse environments (8, 31). This problem has been compounded recently by the emergence of clinical isolates exhibiting intermediate (19-21, 24, 28, 29, 31, 39, 40, 46) or high (5, 11, 47) levels of resistance to glycopeptides, engendering the risk of virtually untreatable infections. Global dispersal of multidrugresistant staphylococci mandates continual development of novel bactericidal agents able to combat such dangerous pathogens.Recent development of ␤-lactams targeting penicillin-binding protein 2Ј (PBP2Ј), which is chiefly responsible for methicillin resistance in S. aureus, repr...

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Section: Discussionmentioning

confidence: 99%

Intensive Therapy with Ceftobiprole Medocaril of Experimental Foreign-Body Infection by Methicillin-Resistant Staphylococcus aureus

Vaudaux

Gjinovci

Bento

et al. 2005

Antimicrob Agents Chemother

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“…The emergence of vancomycin‐resistant strains of Staphylococcus aureus (Walsh and Howe 2002) and Enterococcus faecalis (Paulsen et al 2003), organisms responsible for infective endocarditis, other nosocomial infections, and food poisoning, has exhausted the armamentarium of antibiotics suitable for control of infections by these Gram‐positive cocci. As noted by Ziglam and Nathwani (2003), the emergence worldwide of vancomycin‐resistant entero‐cocci is a grave concern, and new agents are essential to meet this threat. Inhibiting the biosynthesis of isopentenyl diphosphate (IPP), the building block of all isoprenoids, offers potential for the development of antibiotics that target these bacterial pathogens and also the spirochete Borrelia burgdorferi , the causative agent of Lyme disease.…”

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Enterococcus faecalis phosphomevalonate kinase

et al. 2005

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The six enzymes of the mevalonate pathway of isopentenyl diphosphate biosynthesis represent potential for addressing a pressing human health concern, the development of antibiotics against resistant strains of the Gram-positive streptococci. We previously characterized the first four of the mevalonate pathway enzymes of Enterococcus faecalis, and here characterize the fifth, phosphomevalonate kinase (E.C. 2.7.4.2). E. faecalis genomic DNA and the polymerase chain reaction were used to clone DNA thought to encode phosphomevalonate kinase into pET28b(+). Double-stranded DNA sequencing verified the sequence of the recombinant gene. The encoded N-terminal hexahistidine-tagged protein was expressed in Escherichia coli with induction by isopropylthiogalactoside and purified by Ni ++ affinity chromatography, yield 20 mg protein per liter. Analysis of the purified protein by MALDI-TOF mass spectrometry established it as E. faecalis phosphomevalonate kinase. Analytical ultracentrifugation revealed that the kinase exists in solution primarily as a dimer. Assay for phosphomevalonate kinase activity used pyruvate kinase and lactate dehydrogenase to couple the formation of ADP to the oxidation of NADH. Optimal activity occurred at pH 8.0 and at 37°C. The activation energy was ∼5.6 kcal/mol. Activity with Mn ++ , the preferred cation, was optimal at about 4 mM. Relative rates using different phosphoryl donors were 100 (ATP), 3.6 (GTP), 1.6 (TTP), and 0.4 (CTP). K m values were 0.17 mM for ATP and 0.19 mM for (R,S)-5-phosphomevalonate. The specific activity of the purified enzyme was 3.9 mol substrate converted per minute per milligram protein.Applications to an immobilized enzyme bioreactor and to drug screening and design are discussed. (Paulsen et al. 2003), organisms responsible for infective endocarditis, other nosocomial infections, and food poisoning, has exhausted the armamentarium of antibiotics suitable for control of infections by these Grampositive cocci. As noted by Ziglam and Nathwani (2003), the emergence worldwide of vancomycin-resistant enterococci is a grave concern, and new agents are essential to meet this threat. Inhibiting the biosynthesis of isopentenyl diphosphate (IPP), the building block of all isoprenoids, offers potential for the development of antibiotics that target these bacterial pathogens and also the spirochete Borrelia burgdorferi, the causative agent of Lyme disease. Two distinct pathways form IPP, the mevalonate pathway (Fig. 1 Article published online ahead of print. Article and publication date are at Keywords

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“…It represents a serious clinical problem and has created a need for the development of new antimicrobial agents to treat these infections. With the appearance of methicillin-resistant (MR) and vancomycin-resistant (VR) grampositive pathogens, the need for different therapeutic agents is greatly increased, and it has become critical to identify effective agents to treat multidrug-resistant gram-positive infections with novel mechanisms of activity (4,12,13,14,16,20).…”

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confidence: 99%