Activity of novobiocin against methicillin-resistant<i>Staphylococcus</i>aureus

Walsh, Thomas J.; Hansen, Sharon L.; Tatem, Beverly A.; Auger, François A.; Standiford, Harold C.

doi:10.1093/jac/15.4.435

Cited by 23 publications

(21 citation statements)

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“…Novobiocin, a gyrase antagonist, was once used extensively to treat S. aureus infections (36). The location of the novobiocin-binding site on gyrase has yet to be established.…”

Section: Resultsmentioning

confidence: 99%

“…Gyrase inhibitors have been widely used, particularly against Staphylococcus aureus, a gram-positive organism for which few clinically effective agents are available (13). Both ciprofloxacin and novobiocin are active against S. aureus, including methicillin-resistant strains (11,13,25,36), although resistance to fluoroquinolones has rapidly emerged (16,28,29 (2), and Neisseria gonorrhoeae (31), and from Pseudomonas putida (24). …”

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confidence: 99%

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Nucleotide sequence of the Staphylococcus aureus gyrB-gyrA locus encoding the DNA gyrase A and B proteins

1992

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We have determined the nucleotide sequence of a 5.3-kb segment of the Staphylococcus aureus chromosome that includes the gyrA and gyrB genes coding for both subunits of DNA gyrase, the enzyme that catalyzes ATP-dependent DNA supercoiling. The gene order at this locus, dnoA-dnaN-recF-gyrB-gyrA, is similar to that found in the BaciUus subtilis replication origin region. S. aureus recF, gyrB, and gyrA genes are closely spaced, occupy the same reading frame, and may be coordinately expressed. The S. aureus gyrB and gyrA genes encode 640-and 889-residue proteins, respectively, that share strong homology with other bacterial gyrase subunits, notably those from B. subtilis. These results are discussed in regard to the mechanism of DNA gyrase and its role as a target for the 4-quinolones and other antistaphylococcal agents.DNA gyrase, bacterial topoisomerase II, catalyzes ATPdependent DNA supercoiling and is essential for bacterial growth, being involved in DNA replication, transcription, and recombination (9, 37). The Escherichia coli enzyme consists of two A and two B subunits, the 97-and 90-kDa products of the gyrA (48 min) and gyrB genes (82 min), respectively (37). The subunits provide different functions in the DNA strand passage process by which gyrase mediates topological changes in DNA (20). The GyrA subunits form a transient double-strand break in DNA by linking to each complementary DNA strand via . A second DNA duplex is then passed through the gyrase-DNA gate in a process coupled to ATP binding and hydrolysis by the B subunits (20). Several lines of evidence show that the E. coli gyrase subunits are each organized into domains with discrete enzymatic functions (26), as first suggested by studies of a fragment of the gyrase B protein (7).Two classes of drug act by targeting DNA gyrase. Antibacterial 4-quinolones, such as ciprofloxacin, interrupt DNA breakage and resealing by the A subunits (8), whereas the coumarin drugs novobiocin and coumermycin interfere with ATP utilization by the B proteins (10, 32). Gyrase inhibitors have been widely used, particularly against Staphylococcus aureus, a gram-positive organism for which few clinically effective agents are available (13). Both ciprofloxacin and novobiocin are active against S. aureus, including methicillin-resistant strains (11,13,25,36), although resistance to fluoroquinolones has rapidly emerged (16,28,29 (2), and Neisseria gonorrhoeae (31), and from Pseudomonas putida (24). MATERIALS AND METHODSBacterial strains, plasmids, reagents. Cloning of the gyrBgyrA locus from S. aureus 81231 as overlapping inserts contained in plasmids pRH1, pRH2, and pRH3 has been described previously (14). Propagation of the plasmids was in E. coli DH5ao [F-endA1 hsdR17 (rK-MK+) supE44 thi-J recAI gyrA96 rell ]. E. coli XL-1 Blue {endAl hsdRJ7 (rK-MK+) supE44 thi-J X-recAl gyrA96 reLAl (lac) [F' proAB lacIVAMI5 TnlO(Tetr)

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“…Novobiocin, a gyrase antagonist, was once used extensively to treat S. aureus infections (36). The location of the novobiocin-binding site on gyrase has yet to be established.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Nucleotide sequence of the Staphylococcus aureus gyrB-gyrA locus encoding the DNA gyrase A and B proteins

1992

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“…Novobiocin is a bis-hydroxycoumarin compound that is active in vitro against methicillin-resistant staphylococci (90). Like the quinolone compounds, it inhibits DNA gyrase activity (47) …”

Section: Treatment Of Methicillin-resistantmentioning

confidence: 99%

Methicillin-resistant staphylococci: detection methods and treatment of infections

Hackbarth

Chambers

1989

Antimicrob Agents Chemother

113

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“…The MICs and MBCs for 90% of 103 strains from seven different institutions in the United States tested were .0.25 ,ug/ml (49). However, this antibiotic shares with rifampin the potential for emergence of resistance.…”

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confidence: 96%

Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome

Walsh

Standiford

Reboli

et al. 1993

Antimicrob Agents Chemother

134

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Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen in hospitals. Current antimicrobial regimens for eradicating colonizing strains are not well defined and are often complicated by the emergence of resistance. The combination of novobiocin plus rifampin in vitro and in vivo was found to prevent the emergence of resistant populations of initially susceptible strains of MRSA, particularly resistance to rifampin.We therefore studied, in a randomized, double-blind, multicenter comparative trial, the combination of novobiocin plus rifampin versus trimethoprim-sulfamethoxazole (T/S) plus rifampin in order to determine the efficacy of each regimen in eradicating MRSA colonization and to further characterize the host factors involved in the response to this antimicrobial therapy. Among the 126 individuals enrolled in the study, 94 (80 patients; 14 hospital personnel) were evaluable. Among the 94 evaluable subjects, no significant demographic or medical differences existed between the two treatment groups. Successful clearance of the colonizing MRSA strains was achieved in 30 of 45 (67%) subjects receiving novobiocin plus rifampin, whereas successful clearance was achieved in 26 of 49 (53%) subjects treated with T/S plus rifampin (P = 0.18). The emergence of resistance to rifampin developed more frequently in 14% (7 of 49) of subjects treated with T/S plus rifampin than in 2% (1 of 45) of subjects treated with novobiocin plus rifampin (P = 0.04). Restriction endonuclease studies of large plasmid DNA demonstrated that the same strain was present at pretherapy and posttherapy in most refractory cases (24 of 29 [83%] subjects). Among the 56 successfully treated subjects, clearance of MRSA was age dependent: 29 of 36 (80%) subjects in the 18-to 49-year-old age group, 19 of 35 (54%) subjects in the 50-to 69-year-old age group, and 8 of 23 (35%) in the 70-to 94-year-old age group (P < 0.01). Clearance was also site dependent; culture-positive samples from wounds were related to a successful outcome in only 22 (48%) of 46 subjects, whereas culture-positive samples from sites other than wounds (e.g., nares, rectum, and sputum) were associated with a success rate of 34 of 48 (71%) subjects (P = 0.02). Foreign bodies in wounds did not prevent the eradication of MRSA by either regimen. T/S plus rifampin was less effective in clearing pressure wounds compared with other wounds, whereas novobiocin plus rifampin was equally effective in clearing both pressure and other wounds. There were no significant differences in toxicity between the two regimens. Thus, the combination of novobiocin plus rifampin, in comparison with T/S plus rifampin, was more effective in preventing the emergence of resistance to rifampin and demonstrated a trend toward greater activity in clearing the MRSA carrier state. The response to either combination depended on host factors, particularly age and the site of MRSA colonization.

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Activity of novobiocin against methicillin-resistantStaphylococcusaureus

Cited by 23 publications

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Nucleotide sequence of the Staphylococcus aureus gyrB-gyrA locus encoding the DNA gyrase A and B proteins

Nucleotide sequence of the Staphylococcus aureus gyrB-gyrA locus encoding the DNA gyrase A and B proteins

Methicillin-resistant staphylococci: detection methods and treatment of infections

Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome

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