Strong In Vitro Activities of Two New Rifabutin Analogs against Multidrug-Resistant Mycobacterium tuberculosis

ABSTRACT Two new rifabutin analogs, RFA-1 and RFA-2, show high in vitro antimycobacterial activities against Mycobacterium tuberculosis. MIC values of RFA-1 and RFA-2 were ≤0.02 μg/ml against rifamycin-susceptible strains and 0.5 μg/ml against a wide selection of multidrug-resistant strains, compared to ≥50 μg/ml for rifampin and 10 μg/ml for rifabutin. Molecular dynamic studies indicate that the compounds may exert tighter binding to mutants of RNA polymerase that have adapted to the rifamycins.

[1]  R. Wallace,,et al.  Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes , 2011 .

[2]  J. Barluenga,et al.  New rifabutin analogs: synthesis and biological activity against Mycobacterium tuberculosis. , 2006, Bioorganic & medicinal chemistry letters.

[3]  A. Pablos-Mendez,et al.  The global alliance for tuberculosis drug development--accomplishments and future directions. , 2005, Clinics in chest medicine.

[4]  R. O'brien,et al.  New drugs for tuberculosis: current status and future prospects. , 2005, Clinics in chest medicine.

[5]  I. Merino,et al.  NMR spectroscopic analysis of new spiro‐piperidylrifamycins , 2005, Magnetic resonance in chemistry : MRC.

[6]  K. Severinov,et al.  Structural, functional, and genetic analysis of sorangicin inhibition of bacterial RNA polymerase , 2005, The EMBO journal.

[7]  H. Floss,et al.  Rifamycin-mode of action, resistance, and biosynthesis. , 2005, Chemical reviews.

[8]  Brian G. Williams,et al.  Antiretroviral Drugs for Tuberculosis Control in the Era of HIV/AIDS , 2003, Science.

[9]  Christopher Dye,et al.  The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. , 2003, Archives of internal medicine.

[10]  C. Dye,et al.  Worldwide incidence of multidrug-resistant tuberculosis. , 2002, The Journal of infectious diseases.

[11]  A. Telenti,et al.  Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis , 1993, The Lancet.

[12]  L. Marsili,et al.  New rifamycins modified at positions 3 and 4. Synthesis, structure and biological evaluation. , 1981, The Journal of antibiotics.

[13]  E. Bruck,et al.  National Committee for Clinical Laboratory Standards. , 1980, Pediatrics.

[14]  P. Sensi.  Recent progress in the chemistry and biochemistry of rifamycins , 1975 .

[15]  A. Bryskier,et al.  Fluoroquinolones and Tuberculosis: a Review , 2005 .

[16]  A. Bryskier.  Antimicrobial agents: antibacterials and antifungals. , 2005 .

[17]  G. Habermehl,et al.  ReviewPure appl. Chem: Rinehart, K. L., et al. Marine natural products as sources of antiviral, antimicrobial, and antineoplastic Agents. 53, 795 (1981). (K. L. Rinehart, University of Illinois, Urbana, IL 61801, U.S.A.) , 1983 .