TY - JOUR
T1 - In vitro activity of the benzoxazinorifamycin KRM-1648 against drug- susceptible and multidrug-resistant tubercle bacilli
AU - Luna-Herrera, J.
AU - Reddy, M. V.
AU - Gangadharam, P. R.J.
PY - 1995
Y1 - 1995
N2 - We investigated the activity of benzoxazinorifamycin (KRM-1648) against several drug-susceptible and multidrug-resistant strains of tubercle bacilli. Since KRM-1648 is a rifamycin derivative, we included some strains of Mycobacterium tuberculosis resistant to rifampin (RIF) among the multidrug- resistant strains. For RIF-susceptible strains, the MIC of KRM-1648 was much lower than that of RIF (MICs of KRM-1648 and RIF at which 90% of strains are inhibited, ≤0.015 and ≤0.25 μg/ml, respectively). The MBC of KRM-1648 (range, 0.007 to 0.03 μg/ml) was also much lower than that of RIF (range, 0.5 to 1.0 μg/ml). Postantibiotic effect studies with KRM-1648 showed a rapid reduction in the CFU counts with an exposure of 24 h or more, and its sterilizing effect was maintained even up to 21 days thereafter. Parallel postantibiotic effect studies with RIF showed a less significant effect with a faster recovery of growth, and RIF failed to sterilize the organisms even after 72 h of exposure. KRM-1648 at 0.125 and 0.25 μg/ml caused complete inhibition of intracellular growth of M. tuberculosis in J774 A.1 macrophages after 48 h of exposure. After a similar exposure time RIF at a concentration of 0.25 μg/ml caused complete inhibition of growth, but a concentration of 0.125 μg/ml caused only a 50% reduction in growth compared with that of controls at day 7. With 24 h of pulsed exposure of the intracellular organisms to 0.25 μg of the drugs per ml, KRM-1648 caused complete inhibition of intracellular growth, while RIF caused only moderate inhibition of intracellular growth. These findings suggest that KRM-1648 is a potentially useful drug for the treatment of tuberculosis.
AB - We investigated the activity of benzoxazinorifamycin (KRM-1648) against several drug-susceptible and multidrug-resistant strains of tubercle bacilli. Since KRM-1648 is a rifamycin derivative, we included some strains of Mycobacterium tuberculosis resistant to rifampin (RIF) among the multidrug- resistant strains. For RIF-susceptible strains, the MIC of KRM-1648 was much lower than that of RIF (MICs of KRM-1648 and RIF at which 90% of strains are inhibited, ≤0.015 and ≤0.25 μg/ml, respectively). The MBC of KRM-1648 (range, 0.007 to 0.03 μg/ml) was also much lower than that of RIF (range, 0.5 to 1.0 μg/ml). Postantibiotic effect studies with KRM-1648 showed a rapid reduction in the CFU counts with an exposure of 24 h or more, and its sterilizing effect was maintained even up to 21 days thereafter. Parallel postantibiotic effect studies with RIF showed a less significant effect with a faster recovery of growth, and RIF failed to sterilize the organisms even after 72 h of exposure. KRM-1648 at 0.125 and 0.25 μg/ml caused complete inhibition of intracellular growth of M. tuberculosis in J774 A.1 macrophages after 48 h of exposure. After a similar exposure time RIF at a concentration of 0.25 μg/ml caused complete inhibition of growth, but a concentration of 0.125 μg/ml caused only a 50% reduction in growth compared with that of controls at day 7. With 24 h of pulsed exposure of the intracellular organisms to 0.25 μg of the drugs per ml, KRM-1648 caused complete inhibition of intracellular growth, while RIF caused only moderate inhibition of intracellular growth. These findings suggest that KRM-1648 is a potentially useful drug for the treatment of tuberculosis.
UR - http://www.scopus.com/inward/record.url?scp=0028835430&partnerID=8YFLogxK
U2 - 10.1128/aac.39.2.440
DO - 10.1128/aac.39.2.440
M3 - Artículo
SN - 0066-4804
VL - 39
SP - 440
EP - 444
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 2
ER -