The Experts below are selected from a list of 234 Experts worldwide ranked by ideXlab platform
David M. Rothstein - One of the best experts on this subject based on the ideXlab platform.
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Rifalazil and Derivative Compounds Show Potent Efficacy in a Mouse Model of H. pylori Colonization
The Journal of Antibiotics, 2008Co-Authors: David M. Rothstein, John Van Duzer, Steve Mullin, Klari Sirokman, Karen L Söndergaard, Starrla Johnson, Judith K Gwathmey, Christopher K MurphyAbstract:The rifamycin Rifalazil (RFZ), and derivatives (NCEs) were efficacious in a mouse model of Helicobacter pylori colonization. Select NCEs were more active in vitro and showed greater efficacy than RFZ. A systemic component contributes to efficacy.
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Rifalazil Retains Activity Against Rifampin-resistant Mutants of Chlamydia pneumoniae
The Journal of Antibiotics, 2008Co-Authors: David M. Rothstein, Christopher K Murphy, Robert J Suchland, Walter E. StammAbstract:Rifampin-resistant mutants of the obligate intracellular pathogen Chlamydia pneumoniae were isolated and characterized, including strains that contained multiple mutations in the rpoB gene encoding the rifampin binding site. The highest MIC of rifampin against a mutant strain exceeded 100 μg/ml, whereas the highest MIC of Rifalazil was 0.125 μg/ml. Derivatives of Rifalazil (new chemical entities; NCEs) showed from 2∼4 fold lower MICs, as well as 2∼8 fold lower bactericidal concentrations against both wild type and mutant strains when compared with Rifalazil. These results suggest that Rifalazil and NCEs are appropriate therapeutic agents for the treatment of C. pneumoniae infections from the point of view of potency and resistance development.
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Efficacy of Benzoxazinorifamycins in a Mouse Model of Chlamydia pneumoniae Lung Infection
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Lee Ann Campbell, Robert J Suchland, Cho Chou Kuo, David M. RothsteinAbstract:The efficacy of Rifalazil and other benzoxazinorifamycins was tested in a mouse model of lung infection against Chlamydia pneumoniae. Rifalazil and six related new chemical entities all showed efficacy after one dose per day for 3 days at either 3 or 1 mg/kg of body weight.
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Rifalazil and other benzoxazinorifamycins in the treatment of chlamydia-based persistent infections.
Archiv der Pharmazie, 2007Co-Authors: David M. Rothstein, Andrew Sternlicht, John Van Duzer, Steven C. GilmanAbstract:Rifalazil is a benzoxazinorifamycin which inhibits bacterial DNA-dependent RNA polymerase. The benzoxazine ring endows benzoxazinorifamycins with unique physical and chemical characteristics which favor the use of Rifalazil and derivatives in treating diseases caused by the obligate intracellular pathogens of the genus chlamydia. Minimal inhibitory concentrations of benzoxazinorifamycins against chlamydia are in the pg/mL range. These compounds have potential as monotherapeutic agents to treat chlamydia-associated disease because they retain activity against chlamydia strains resistant to currently approved rifamycins such as rifampin. A pivotal clinical trial with Rifalazil has been initiated for the treatment of peripheral arterial disease. The rationale for this innovative use of Rifalazil, including the association of C. pneumoniae in atherosclerotic plaque formation, as well as Rifalazil's potency and efficacy against chlamydia in both preclinical and clinical studies, is discussed. Other benzoxazino derivatives may have utility as stand-alone topical antibacterials or combination antibacterials to treat serious Gram-positive infections. None of the benzoxazinorifamycins examined to date induce the cytochrome P450 3A4 enzyme. This is in contrast to currently approved rifamycins which are strong inducers of P450 enzymes, resulting in drug-drug interactions that limit the clinical utility of this drug class.
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Development potential of Rifalazil and other benzoxazinorifamycins.
Expert Opinion on Investigational Drugs, 2006Co-Authors: David M. Rothstein, Andrew Sternlicht, Christo Shalish, Christopher K Murphy, Lee Ann CampbellAbstract:Rifalazil and other benzoxazinorifamycins (new chemical entities [NCEs]) are rifamycins that contain a distinct planar benzoxazine ring. Rifalazil has excellent antibacterial activity, high intracellular levels and high tissue penetration, which are attributes that favour its use in treating diseases caused by the obligate intracellular pathogens of the genus Chlamydia. Recent studies have shown that Rifalazil has efficacy in the treatment of human sexually transmitted disease caused by Chlamydia trachomatis. The extraordinary potency of Rifalazil and other NCEs, such as ABI-0043, extends to the related microorganism, C. pneumoniae, a respiratory pathogen that can disseminate and persist chronically in the vasculature, resulting in increased plaque formation in animal studies. A pivotal clinical trial with Rifalazil has been initiated for the treatment of peripheral arterial disease. Other opportunities include gastric ulcer disease caused by Helicobacter pylori and antibiotic-associated colitis caused by...
Christopher K Murphy - One of the best experts on this subject based on the ideXlab platform.
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Rifalazil Retains Activity Against Rifampin-resistant Mutants of Chlamydia pneumoniae
The Journal of Antibiotics, 2008Co-Authors: David M. Rothstein, Christopher K Murphy, Robert J Suchland, Walter E. StammAbstract:Rifampin-resistant mutants of the obligate intracellular pathogen Chlamydia pneumoniae were isolated and characterized, including strains that contained multiple mutations in the rpoB gene encoding the rifampin binding site. The highest MIC of rifampin against a mutant strain exceeded 100 μg/ml, whereas the highest MIC of Rifalazil was 0.125 μg/ml. Derivatives of Rifalazil (new chemical entities; NCEs) showed from 2∼4 fold lower MICs, as well as 2∼8 fold lower bactericidal concentrations against both wild type and mutant strains when compared with Rifalazil. These results suggest that Rifalazil and NCEs are appropriate therapeutic agents for the treatment of C. pneumoniae infections from the point of view of potency and resistance development.
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Rifalazil and Derivative Compounds Show Potent Efficacy in a Mouse Model of H. pylori Colonization
The Journal of Antibiotics, 2008Co-Authors: David M. Rothstein, John Van Duzer, Steve Mullin, Klari Sirokman, Karen L Söndergaard, Starrla Johnson, Judith K Gwathmey, Christopher K MurphyAbstract:The rifamycin Rifalazil (RFZ), and derivatives (NCEs) were efficacious in a mouse model of Helicobacter pylori colonization. Select NCEs were more active in vitro and showed greater efficacy than RFZ. A systemic component contributes to efficacy.
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Development potential of Rifalazil and other benzoxazinorifamycins.
Expert Opinion on Investigational Drugs, 2006Co-Authors: David M. Rothstein, Andrew Sternlicht, Christo Shalish, Christopher K Murphy, Lee Ann CampbellAbstract:Rifalazil and other benzoxazinorifamycins (new chemical entities [NCEs]) are rifamycins that contain a distinct planar benzoxazine ring. Rifalazil has excellent antibacterial activity, high intracellular levels and high tissue penetration, which are attributes that favour its use in treating diseases caused by the obligate intracellular pathogens of the genus Chlamydia. Recent studies have shown that Rifalazil has efficacy in the treatment of human sexually transmitted disease caused by Chlamydia trachomatis. The extraordinary potency of Rifalazil and other NCEs, such as ABI-0043, extends to the related microorganism, C. pneumoniae, a respiratory pathogen that can disseminate and persist chronically in the vasculature, resulting in increased plaque formation in animal studies. A pivotal clinical trial with Rifalazil has been initiated for the treatment of peripheral arterial disease. Other opportunities include gastric ulcer disease caused by Helicobacter pylori and antibiotic-associated colitis caused by...
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Enhanced Activity of Rifalazil in Combination with Levofloxacin, Linezolid, or Mupirocin against Staphylococcus aureus In Vitro
The Journal of Antibiotics, 2006Co-Authors: Marcia S. Osburne, Christopher K Murphy, David M. RothsteinAbstract:Rifalazil is a potent second-generation ansamycin that kills bacterial cells by inhibiting the β subunit of RNA polymerase. Rifalazil has several improved properties compared with rifampicin, but retains rifampicin's propensity to develop resistant mutants at high frequency. To explore strategies to overcome resistance development, we studied the effects of Rifalazil in combination with several different antibiotics in an in vitro time-kill model, against both log phase and stationary phase Staphylococcus aureus cells. Experiments were carried out at high initial cell density so that the frequency and proliferation of resistant mutants could be monitored. We found that each combination was advantageous in terms of enhanced killing and the suppression of mutants, compared with each drug used alone. None of the three combinations was effective against stationary phase cells.
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In Vitro Time-kill Activities of Rifalazil, Alone and in Combination with Vancomycin, against Logarithmic and Stationary Cultures of Staphylococcus aureus
The Journal of Antibiotics, 2006Co-Authors: Marcia S. Osburne, David M. Rothstein, Ronnie Farquhar, Christopher K MurphyAbstract:Rifalazil is a novel rifamycin that, like other members of this class, inhibits bacterial transcription by targeting the β subunit of prokaryotic DNA-dependent RNA polymerase. To address the high-frequency resistance seen with rifamycins, we assessed the ability of Rifalazil, alone and in combination with vancomycin, to both kill cells and to suppress the appearance of resistant mutants in log and stationary phase Staphylococcus aureus cultures, using high cell densities in an in vitro kill curve model. We found that 1) Rifalazil alone killed log-phase cultures more rapidly than rifampicin, but both drugs quickly selected for resistant mutants, 2) co-treatment of log phase cultures with Rifalazil and vancomycin increased bacterial killing by about 3-Log_10 over either drug used alone and delayed the appearance of rifamycin-resistant mutants, 3) Rifalazil and vancomycin in combination killed stationary phase cultures by 3∼4 Log_10 by 48 hours.
Walter E. Stamm - One of the best experts on this subject based on the ideXlab platform.
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Rifalazil Retains Activity Against Rifampin-resistant Mutants of Chlamydia pneumoniae
The Journal of Antibiotics, 2008Co-Authors: David M. Rothstein, Christopher K Murphy, Robert J Suchland, Walter E. StammAbstract:Rifampin-resistant mutants of the obligate intracellular pathogen Chlamydia pneumoniae were isolated and characterized, including strains that contained multiple mutations in the rpoB gene encoding the rifampin binding site. The highest MIC of rifampin against a mutant strain exceeded 100 μg/ml, whereas the highest MIC of Rifalazil was 0.125 μg/ml. Derivatives of Rifalazil (new chemical entities; NCEs) showed from 2∼4 fold lower MICs, as well as 2∼8 fold lower bactericidal concentrations against both wild type and mutant strains when compared with Rifalazil. These results suggest that Rifalazil and NCEs are appropriate therapeutic agents for the treatment of C. pneumoniae infections from the point of view of potency and resistance development.
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A randomized, double-blind study comparing single-dose Rifalazil with single-dose azithromycin for the empirical treatment of nongonococcal urethritis in men
Sexually Transmitted Diseases, 2007Co-Authors: Walter E. Stamm, Byron E. Batteiger, William M. Mccormack, Patricia A. Totten, Andrew Sternlicht, Nancy M. KivelAbstract:Objectives: To determine the safety and effectiveness of single-dose Rifalazil, a new rifamycin, for the treatment of nongonococcal urethritis (NGU). Study Design: Randomized, double-blind trial comparing Rifalazil, 2.5, 12.5 or 25 mg, with 1.0 g azithromycin for the treatment of NGU. One hundred and seventy men were evaluated for Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma genitalium infection before therapy and 2- and 5-weeks posttreatment. Results: C. trachomatis, M. genitalium, and U. urealyticum were present in 42%, 24%, and 28% of subjects, respectively. Microbiologic eradication of C. trachomatis with Rifalazil 25 mg at 2- and 5- weeks was 85% and 83%, respectively. Rifalazil was ineffective in eradicating M. genitalium and U. urealyticum. Overall clinical cure rates at 2-and 5-weeks were 86% (95% CI 67-96) and 59% (39-78) in the Rifalazil-treated 25 mg group, and 77% (56-91) and 63% (41-81) in the azithromycin-treated group. Conclusions: Rifalazil was well tolerated and eradicates C. trachomatis but not M. genitalium and U. ureaplasma in men with NGU.
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Rifalazil Pretreatment of Mammalian Cell Cultures Prevents Subsequent Chlamydia Infection
Antimicrobial Agents and Chemotherapy, 2006Co-Authors: Robert J Suchland, David M. Rothstein, Kara Brown, Walter E. StammAbstract:Chlamydia species are widely disseminated obligate intracellular pathogens that primarily cause urogenital, ocular, and respiratory infections. In these studies, we show that exposing mammalian cells to antibacterial agents prior to Chlamydia inoculation protects the host cells against subsequent challenge by chlamydiae (the protective effect [PE]). Rifalazil exhibited a considerably stronger PE than did azithromycin, rifampin, doxycycline, and ofloxacin. Specifically, 0.002 μg/ml Rifalazil incubated for 1 day with a monolayer of McCoy cells was sufficient to protect against a challenge 2 days later with Chlamydia trachomatis serovar D (UW-3). The PE was observed with five different mammalian cell lines and with a variety of C. trachomatis and Chlamydia pneumoniae isolates. The duration of the PE was 6 to 12 days for Rifalazil (depending on the cell line), a maximum of 3 days for azithromycin, and less than a day for the other drugs tested. For Rifalazil, the PE was shown to be mediated by inhibition of the chlamydial RNA polymerase since mutants with altered RNA polymerases had correspondingly altered PEs. These results suggest that Rifalazil may be unique in its ability to prevent infection with obligate intracellular pathogens for a considerable time after treatment. This characteristic may be of particular public health value in reducing reinfection with chlamydiae.
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rifampin resistant rna polymerase mutants of chlamydia trachomatis remain susceptible to the ansamycin Rifalazil
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Robert J Suchland, Walter E. Stamm, Erick Denamur, Agnes Bourillon, David M. RothsteinAbstract:Stable, homotypic mutants of Chlamydia trachomatis for which MICs of rifampin and Rifalazil are elevated were isolated by serial passage at sub-MIC concentrations of these compounds. An alternative approach, in which Chlamydia cells were incubated and subsequently passaged three times, all in the presence of the selective agent at concentrations above the MIC, appeared to be a more effective means of selecting for mutants. In every instance where an elevation in the MIC occurred, one or more mutations in the rpoB gene, encoding the rifampin binding site, were detected. With one exception, all rpoB mutants that contained a single mutation conferred lower levels of resistance than mutants containing multiple mutations. Some rpoB mutations conferred very high levels of resistance to rifampin, up to 512 μg/ml. In all cases, mutants remained susceptible to concentrations of Rifalazil at or below 0.064 μg/ml. Thus, Rifalazil, a compound that is extremely potent against Chlamydia wild-type cells (MIC of 0.00025 μg/ml), may also protect against the selection of mutants at physiologically achievable concentrations.
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Activities of Rifamycin Derivatives against Wild-Type and rpoB Mutants of Chlamydia trachomatis
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Minsheng Xia, David M. Rothstein, Robert J Suchland, Kara Brown, John Van Duzer, Joli A. Carswell, Debra K Buxton, Walter E. StammAbstract:Rifalazil, a semisynthetic rifamycin, was shown previously to have exceptional potency against Chlamydia trachomatis (MIC of 0.00025 μg/ml). We therefore tested 250 additional rifamycin derivatives and identified 12 with activities that are eightfold more potent than that of Rifalazil. These compounds also showed exceptional activities against rifampin-resistant strains that carry missense mutations in the rpoB gene. The antimicrobial potency and intracellular penetration of these agents suggest their potential in treatment of chlamydial infections.
Robert J Suchland - One of the best experts on this subject based on the ideXlab platform.
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Rifalazil Retains Activity Against Rifampin-resistant Mutants of Chlamydia pneumoniae
The Journal of Antibiotics, 2008Co-Authors: David M. Rothstein, Christopher K Murphy, Robert J Suchland, Walter E. StammAbstract:Rifampin-resistant mutants of the obligate intracellular pathogen Chlamydia pneumoniae were isolated and characterized, including strains that contained multiple mutations in the rpoB gene encoding the rifampin binding site. The highest MIC of rifampin against a mutant strain exceeded 100 μg/ml, whereas the highest MIC of Rifalazil was 0.125 μg/ml. Derivatives of Rifalazil (new chemical entities; NCEs) showed from 2∼4 fold lower MICs, as well as 2∼8 fold lower bactericidal concentrations against both wild type and mutant strains when compared with Rifalazil. These results suggest that Rifalazil and NCEs are appropriate therapeutic agents for the treatment of C. pneumoniae infections from the point of view of potency and resistance development.
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Efficacy of Benzoxazinorifamycins in a Mouse Model of Chlamydia pneumoniae Lung Infection
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Lee Ann Campbell, Robert J Suchland, Cho Chou Kuo, David M. RothsteinAbstract:The efficacy of Rifalazil and other benzoxazinorifamycins was tested in a mouse model of lung infection against Chlamydia pneumoniae. Rifalazil and six related new chemical entities all showed efficacy after one dose per day for 3 days at either 3 or 1 mg/kg of body weight.
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Rifalazil Pretreatment of Mammalian Cell Cultures Prevents Subsequent Chlamydia Infection
Antimicrobial Agents and Chemotherapy, 2006Co-Authors: Robert J Suchland, David M. Rothstein, Kara Brown, Walter E. StammAbstract:Chlamydia species are widely disseminated obligate intracellular pathogens that primarily cause urogenital, ocular, and respiratory infections. In these studies, we show that exposing mammalian cells to antibacterial agents prior to Chlamydia inoculation protects the host cells against subsequent challenge by chlamydiae (the protective effect [PE]). Rifalazil exhibited a considerably stronger PE than did azithromycin, rifampin, doxycycline, and ofloxacin. Specifically, 0.002 μg/ml Rifalazil incubated for 1 day with a monolayer of McCoy cells was sufficient to protect against a challenge 2 days later with Chlamydia trachomatis serovar D (UW-3). The PE was observed with five different mammalian cell lines and with a variety of C. trachomatis and Chlamydia pneumoniae isolates. The duration of the PE was 6 to 12 days for Rifalazil (depending on the cell line), a maximum of 3 days for azithromycin, and less than a day for the other drugs tested. For Rifalazil, the PE was shown to be mediated by inhibition of the chlamydial RNA polymerase since mutants with altered RNA polymerases had correspondingly altered PEs. These results suggest that Rifalazil may be unique in its ability to prevent infection with obligate intracellular pathogens for a considerable time after treatment. This characteristic may be of particular public health value in reducing reinfection with chlamydiae.
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rifampin resistant rna polymerase mutants of chlamydia trachomatis remain susceptible to the ansamycin Rifalazil
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Robert J Suchland, Walter E. Stamm, Erick Denamur, Agnes Bourillon, David M. RothsteinAbstract:Stable, homotypic mutants of Chlamydia trachomatis for which MICs of rifampin and Rifalazil are elevated were isolated by serial passage at sub-MIC concentrations of these compounds. An alternative approach, in which Chlamydia cells were incubated and subsequently passaged three times, all in the presence of the selective agent at concentrations above the MIC, appeared to be a more effective means of selecting for mutants. In every instance where an elevation in the MIC occurred, one or more mutations in the rpoB gene, encoding the rifampin binding site, were detected. With one exception, all rpoB mutants that contained a single mutation conferred lower levels of resistance than mutants containing multiple mutations. Some rpoB mutations conferred very high levels of resistance to rifampin, up to 512 μg/ml. In all cases, mutants remained susceptible to concentrations of Rifalazil at or below 0.064 μg/ml. Thus, Rifalazil, a compound that is extremely potent against Chlamydia wild-type cells (MIC of 0.00025 μg/ml), may also protect against the selection of mutants at physiologically achievable concentrations.
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Activities of Rifamycin Derivatives against Wild-Type and rpoB Mutants of Chlamydia trachomatis
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Minsheng Xia, David M. Rothstein, Robert J Suchland, Kara Brown, John Van Duzer, Joli A. Carswell, Debra K Buxton, Walter E. StammAbstract:Rifalazil, a semisynthetic rifamycin, was shown previously to have exceptional potency against Chlamydia trachomatis (MIC of 0.00025 μg/ml). We therefore tested 250 additional rifamycin derivatives and identified 12 with activities that are eightfold more potent than that of Rifalazil. These compounds also showed exceptional activities against rifampin-resistant strains that carry missense mutations in the rpoB gene. The antimicrobial potency and intracellular penetration of these agents suggest their potential in treatment of chlamydial infections.
Marcia S. Osburne - One of the best experts on this subject based on the ideXlab platform.
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Enhanced Activity of Rifalazil in Combination with Levofloxacin, Linezolid, or Mupirocin against Staphylococcus aureus In Vitro
The Journal of Antibiotics, 2006Co-Authors: Marcia S. Osburne, Christopher K Murphy, David M. RothsteinAbstract:Rifalazil is a potent second-generation ansamycin that kills bacterial cells by inhibiting the β subunit of RNA polymerase. Rifalazil has several improved properties compared with rifampicin, but retains rifampicin's propensity to develop resistant mutants at high frequency. To explore strategies to overcome resistance development, we studied the effects of Rifalazil in combination with several different antibiotics in an in vitro time-kill model, against both log phase and stationary phase Staphylococcus aureus cells. Experiments were carried out at high initial cell density so that the frequency and proliferation of resistant mutants could be monitored. We found that each combination was advantageous in terms of enhanced killing and the suppression of mutants, compared with each drug used alone. None of the three combinations was effective against stationary phase cells.
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In Vitro Time-kill Activities of Rifalazil, Alone and in Combination with Vancomycin, against Logarithmic and Stationary Cultures of Staphylococcus aureus
The Journal of Antibiotics, 2006Co-Authors: Marcia S. Osburne, David M. Rothstein, Ronnie Farquhar, Christopher K MurphyAbstract:Rifalazil is a novel rifamycin that, like other members of this class, inhibits bacterial transcription by targeting the β subunit of prokaryotic DNA-dependent RNA polymerase. To address the high-frequency resistance seen with rifamycins, we assessed the ability of Rifalazil, alone and in combination with vancomycin, to both kill cells and to suppress the appearance of resistant mutants in log and stationary phase Staphylococcus aureus cultures, using high cell densities in an in vitro kill curve model. We found that 1) Rifalazil alone killed log-phase cultures more rapidly than rifampicin, but both drugs quickly selected for resistant mutants, 2) co-treatment of log phase cultures with Rifalazil and vancomycin increased bacterial killing by about 3-Log_10 over either drug used alone and delayed the appearance of rifamycin-resistant mutants, 3) Rifalazil and vancomycin in combination killed stationary phase cultures by 3∼4 Log_10 by 48 hours.
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In vitro time-kill activities of Rifalazil, alone and in combination with vancomycin, against logarithmic and stationary cultures of Staphylococcus aureus.
The Journal of Antibiotics, 2006Co-Authors: Marcia S. Osburne, David M. Rothstein, Ronnie Farquhar, Christopher K MurphyAbstract:Rifalazil is a novel rifamycin that, like other members of this class, inhibits bacterial transcription by targeting the beta subunit of prokaryotic DNA-dependent RNA polymerase. To address the high-frequency resistance seen with rifamycins, we assessed the ability of Rifalazil, alone and in combination with vancomycin, to both kill cells and to suppress the appearance of resistant mutants in log and stationary phase Staphylococcus aureus cultures, using high cell densities in an in vitro kill curve model. We found that (1) Rifalazil alone killed log-phase cultures more rapidly than rifampicin, but both drugs quickly selected for resistant mutants, (2) co-treatment of log phase cultures with Rifalazil and vancomycin increased bacterial killing by about 3-Log10 over either drug used alone and delayed the appearance of rifamycin-resistant mutants, (3) Rifalazil and vancomycin in combination killed stationary phase cultures
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In Vitro Activity of Novel Rifamycins against Rifamycin-Resistant Staphylococcus aureus
Antimicrobial Agents and Chemotherapy, 2006Co-Authors: Christopher K Murphy, Michael H. Cynamon, Marcia S. Osburne, John Van Duzer, Steve Mullin, Jim Siedlecki, Kathy Kerstein, David M. RothsteinAbstract:We describe novel rifamycin derivatives (new chemical entities [NCEs]) that retain significant activity against a comprehensive collection of Staphylococcus aureus strains that are resistant to rifamycins. This collection of resistant strains contains 21 of the 26 known single-amino-acid alterations in RpoB, the target of rifamycins. Some NCEs also demonstrated a lower frequency of resistance development than rifampin and Rifalazil in S. aureus as measured in a resistance emergence test. When assayed for activity against the strongest rifamycin-resistant mutants, several NCEs had MICs of 2 μg/ml, in contrast to MICs of rifampin and Rifalazil, which were 512 μg/ml for the same strains. The properties of these NCEs therefore demonstrate a significant improvement over those of earlier rifamycins, which have been limited primarily to combination therapy due to resistance development, and suggest a potential use of these NCEs for monotherapy in several clinical indications.
