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In Vitro and In Vivo Properties of Ro 63-9141, a Novel Broad-Spectrum Cephalosporin with Activity against Methicillin-Resistant Staphylococci
- P. Hebeisen, I. Heinze-Krauss, P. Angehrn, P. Hohl, M. Page, R. Then
- Biology, MedicineAntimicrobial Agents and Chemotherapy
- 1 March 2001
The potential utility of Ro 63-9141 for the therapy of infections caused by susceptible pathogens, including MRSA, is suggested and a water-soluble prodrug, Ro 65-5788, is considered for development.
Structure and function of the dihydropteroate synthase from Staphylococcus aureus.
The three-dimensional structure of the substrate analogue binary complex could give important insight into the molecular mechanism of this enzyme, which defies a simple interpretation of their roles in resistance.
A single amino acid substitution in Staphylococcus aureus dihydrofolate reductase determines trimethoprim resistance.
Critical evidence concerning the resistance mechanism has been provided by NMR spectral analyses of 15N-labelled TMP in the ternary complexes of both wild-type and mutant enzyme, and studies show that the mutation results in loss of a hydrogen bond between the 4-amino group of TMP and the carbonyl oxygen of Leu5.
DNA and RNA synthesis: antifolates.
Trapping of nonhydrolyzable cephalosporins by cephalosporinases in Enterobacter cloacae and Pseudomonas aeruginosa as a possible resistance mechanism
Findings corroborate the assumption that binding of nonhydrolyzable cephalosporins, rather than hydrolysis by cep Halosporinases, may play an important role in resistance to these agents and other newer cep HALsporins in Enterobacteriaceae, as well as in other gram-negative bacteria.
Mechanisms of resistance to trimethoprim, the sulfonamides, and trimethoprim-sulfamethoxazole.
- R. Then
- Biology, ChemistryReviews of infectious diseases
- 1 March 1982
Several mechanisms of resistance that have rarely been discussed in the past are discussed, including metabolic alteration of trimethoprim or the sulfonamides and hyperproduction of p-aminobenzoic acid, and on the simultaneous presence of more than one mechanism.
History and future of antimicrobial diaminopyrimidines.
- R. Then
- Biology, ChemistryJournal of chemotherapy
- 1 December 1993
Key milestones in the application of antimicrobial DHFR inhibitors were the introduction of TMP alone in 1972, the launch of a new combination of tetroxoprim, a close TMP-analog, with sulfadiazine, and the successful clinical trials with brodimopim, which proved clinically efficacious and safe with once-daily low dose monotherapy.
Nature of trimethoprim-induced death in Escherichia coli.
Characterization of the gene for the chromosomal dihydrofolate reductase (DHFR) of Staphylococcus epidermidis ATCC 14990: the origin of the trimethoprim-resistant S1 DHFR from Staphylococcus aureus?
Site-directed mutagenesis and kinetic analysis of the purified enzymes suggest that a single Phe-->Tyr change at position 98 is the major determinant of trimethoprim resistance.
Antimicrobial Dihydrofolate Reductase Inhibitors - Achievements and Future Options: Review
- R. Then
- BiologyJournal of chemotherapy
- 1 February 2004
There are excellent chances for new drugs in this field, and they are thought to increase by limiting the spectrum of activity, whereas trimethoprim seems to present the optimum which can be achieved for a broad spectrum antibacterial agent.