Activities of TMC207, Rifampin, and Pyrazinamide against Mycobacterium tuberculosis Infection in Guinea Pigs

Abstract

The experimental compound TMC207 is showing promise against infections caused by Mycobacterium tuberculosis both in a variety of animal studies and in the field. In this study, we used the guinea pig model, a species that shows several similarities to human tuberculosis, including the hallmark of primary granuloma necrosis, to determine the efficacy of a combination regimen combining TMC207 with rifampin and pyrazinamide. This drug regimen rapidly reduced the bacterial load in the lungs to undetectable levels by 8 weeks of treatment. This reduction was associated with a substantial improvement in lung pathology, but despite this effect areas of residual necrosis still remained. In the draining lymph nodes, however, tissue damage was rapid and not significantly reversed by the drug treatment. Approximately 10 to 11 months after the treatment had ended, the animals began to trigger a Karnovsky scale indicating bacterial regrowth and potential relapse, an event confirmed by the new development of both pulmonary and extrapulmonary granulomatous lesions. Interestingly, a similar rate of relapse was also seen in animals receiving 24 weeks of rifampin, pyrazinamide, and isoniazid standard chemotherapy. These data indicate that TMC207 could be a useful addition to current treatment regimens for tuberculosis.The increasing incidence of drug-resistant forms of Mycobacterium tuberculosis, now thought to exceed half a million new cases a year (8,10,11,26), further complicates the critical need to discover new antituberculosis drugs. Equally troubling, newly emerging evidence suggests that a significant percentage of new clinical isolates of M. tuberculosis are of extremely high virulence (8). Within the current drug discovery pipeline (12), a particularly attractive new candidate is the diarylquinolone TMC207 (2). This investigational drug potently inhibits the mycobacterial enzyme complex ATP synthase, thus interfering with energy production and homeostasis. As a consequence, TMC207 is highly active against both drug-sensitive and drugresistant isolates of M. tuberculosis.In animal studies, the majority of data has been obtained from the mouse model, where TMC207 has activity equivalent to, and synergizes with, standard rifampin, isoniazid, and pyrazinamide therapy (RHZ) (3,13,14,17,18,30). However, although the mouse is an excellent and cost-effective screening tool (15), it lacks elements of the disease pathogenesis in humans, including granulomatous lymphadenitis, lymphangitis, and the development of both pulmonary and extrapulmonary lesions exhibiting caseous necrosis with dystrophic calcification (15). In contrast, the guinea pig model of tuberculosis mimics multiple elements of the pathogenesis of the disease in humans (4, 6, 7).Virtually all studies evaluating drug efficacy in animal models utilize the laboratory strains M. tuberculosis H37Rv or Erdman. However, it is becoming increasingly apparent that newly emerging isolates are of very high virulence, including the W-Beijing family of M. tuberculosis, which is no...

Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs

“…In the current study, mycobacteria were still detectable in the spleens of guinea pigs assessed at relapse after 2 months of RHZ or PHZ, indicating that TB infection was not eradicated in these animals. Difficulty in sterilizing M. tuberculosis-infected guinea pig tissues was also observed by Shang et al, who showed that although a combination regimen containing the novel diarylquinolone TMC207 with R and Z rapidly reduced the bacillary load in the lungs to undetectable levels by 8 weeks of treatment, more than one fifth of animals developed clinical relapse as late as 11 months after the treatment was discontinued (32). The reason for the inferior activity of the two rifamycin-containing regimens against M. tuberculosis in the spleens relative to the lungs observed in the current study requires further investigation.…”

Susceptibility of Mycobacterium abscessus to Antimycobacterial Drugs in Preclinical Models

“…Studies using multiple animal models have shown that bedaquiline is efficacious against M. tuberculosis, Mycobacterium leprae, and to some extent M. avium (25,(35)(36)(37). Bedaquiline potently inhibits the mycobacterial enzyme complex ATP synthase, thus interfering with energy production and homeostasis.…”

Production of valuable compounds by molds and yeasts

“…A new and approved cephalosporin is ceftobiprole that is active against methicillin-resistant S. aureus and is not hydrolyzed by a number of β-lactamases from Gram-positive bacteria. 100 Another antibiotic of note is cerulenin, an antifungal agent produced by Acremonium caerelens. It was the first inhibitor of fatty acid biosynthesis discovered.…”