In vitro and in vivo activities of the benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis

Abstract

The in vitro and in vivo activities of a new benzoxazinorifamycin, KRM-1648 (KRM), against Mycobacterium tuberculosis were studied. The MIC at which 50% of the isolates are inhibited (MIC 50 ) and the MIC 90 of KRM for 30 fresh isolates of M. tuberculosis measured by the BACTEC 460 TB System were 0.016 and 2 g/ml, respectively. These values were much lower than those for rifampin (RMP), which were 4 and >128 g/ml, respectively, and considerably lower than those for rifabutin (RBT), which were 0.125 and 8 g/ml, respectively. A correlational analysis of the MICs of these drugs for the clinical isolates revealed the presence of crossresistance of the organisms to KRM and either RMP or RBT although the MICs of KRM were distributed over a much lower range than were those of the other two drugs. KRM and RMP at concentrations of 1 to 10 g/ml almost completely inhibited the bacterial growth of RMP-sensitive strains (H 37 Rv, Kurono, and Fujii) of M. tuberculosis phagocytosed in macrophage-derived J774.1 cells. KRM was more active than RMP in inhibiting the growth of the RMP-resistant (MIC ‫؍‬ 8 g/ml) Kurata strain but failed to show such an effect against the RMP-resistant (MIC >128 g/ml) Watanabe strain. When KRM was given to M. tuberculosis-infected mice at dosages of 5 to 20 mg/kg of body weight by gavage, once daily six times per week from day 1 after infection, it was much more efficacious than RMP against infections induced in mice by the RMP-sensitive Kurono strain, as measured by a reduction of rates of mortality, a reduction of the frequency and extent of gross lung lesions, histopathological changes in lung tissues, and a decrease in the bacterial loads in the lungs and spleens of infected mice. KRM also displayed significant therapeutic efficacy against infection induced by the RMPresistant Kurata strain, while neither KRM nor RMP was efficacious against infection by the RMP-resistant Watanabe strain. In the case of infection with the Kurono strain, the efficacy of the drugs in prolonging the time of survival was in the order KRM, RBT, RMP. KRM was much more efficacious than RMP, when given at 1-to 4-week intervals. These findings suggest that KRM may be useful for the clinical treatment of tuberculosis contracted through RMP-sensitive strains, even when it is administered at long intervals.

Efficacy of Novel Rifamycin Derivatives against Rifamycin-Sensitive and -Resistant Staphylococcus aureus Isolates in Murine Models of Infection

“…The potency of rifalazil and the other rifamycins derives from their specific inhibition of bacterial RNA polymerase (6). Preclinical animal studies suggest that rifalazil has efficacy against Chlamydia pneumoniae (9), Clostridium difficile (2), Mycobacterium tuberculosis (8,19,20), and Staphylococcus aureus (7). In addition, rifalazil has been tested in phase 2 human clinical trials for the treatment of tuberculosis (5) L-992b, 2004).…”

Comparative Profiles of Intramacrophage Behavior of Mycobacterium tuberculosis and Mycobacterium avium Complex with Different Levels of Virulence

“…The moderate-virulence N-260 strain induced greater RNI production than the low-virulence N-444 strain did. The present study indicated that MAC organisms are capable of persisting or replicating in murine MΦs for long periods, as with MTB, even though MAC is less virulent to mice than MTB is on the basis of the rate of bacterial growth at the infection sites, the incidence of gross lesions in the lungs, and the mortality of infected mice (6,14,18,19). Notably, MAC N-260 with moderate virulence in mice could grow in murine MΦs more rapidly than the virulent MTB H37Rv strain did, and slow but steady growth within MΦs was observed even in the case of MAC N-444 strain with low virulence in mice (Fig.…”

Prospects for development of new antimycobacterial drugs

“…[117][118][119][120][121][122][123] On the basis of the MIC, KRM is 16 to 512 times more active against these organisms than RFP, and 2 to 8 times more active than RBT. 117,118,121 Similar results were obtained with a radiometric method, using the BACTEC 460 TB system (Becton Dickinson Diagnostic Instrument Systems, Sparks, USA). 118 Correlational analysis of MICs for KRM for individual isolates of MTB and MICs for RFP and RBT indicated the presence of crossresistance in most organisms to KRM and RFP and to KRM and RBT.…”