Preclinical Efficacy Testing of New Drug Candidates

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ABSTRACT

This is a review of the preclinical efficacy testing of new antituberculosis drug candidates. It describes existing dynamic in vitro and in vivo models of antituberculosis chemotherapy and their utility in preclinical evaluations of promising new drugs and combination regimens, with an effort to highlight recent developments. Emphasis is given to the integration of quantitative pharmacokinetic/pharmacodynamic analyses and the impact of lesion pathology on drug efficacy. Discussion also includes in vivo models of chemotherapy of latent tuberculosis infection.

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The association between sterilizing activity and drug distribution into tuberculosis lesions

Brendan Prideaux, Laura Via, Matthew D. Zimmerman … (2015)

Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a MALDI mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside 1 . In contrast, moxifloxacin which is active in vitro against persisters, a sub-population of Mycobacterium tuberculosis that persists in specific niches under drug pressure, and achieved treatment shortening in mice 2 , does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We also suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration contributes to treatment outcome has wide implications for TB.

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Douglas Young, JoAnne Flynn, Helena Boshoff … (2009)

Immunological tests provide evidence of latent tuberculosis in one third of the global population, which corresponds to more than two billion individuals. Latent tuberculosis is defined by the absence of clinical symptoms but carries a risk of subsequent progression to clinical disease, particularly in the context of co-infection with HIV. In this Review we discuss the biology of latent tuberculosis as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria. We then show how this model can be used to develop a rational programme to discover effective drugs for the eradication of M. tuberculosis infection.

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Christopher Dye, Philippe Glaziou, Katherine Floyd … (2012)

The target for TB elimination is to reduce annual incidence to less than one case per million population by 2050. Meeting that target requires a 1,000-fold reduction in incidence in little more than 35 years. This can be achieved only by combining the effective treatment of active TB-early case detection and high cure rates to interrupt transmission-with methods to prevent new infections and to neutralize existing latent infections. Vigorous implementation of the WHO Stop TB Strategy is needed to achieve the former, facilitated by the effective supply of, and demand for, health services. The latter calls for new technology, including biomarkers of TB risk, diagnostics, drugs, and vaccines. An important milestone en route to elimination will be reached when there is less than 1 TB death per 100,000 population, marking entry into the elimination phase. This landmark can be reached by many countries within 1-2 decades.

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Author and article information

Journal

Title: Microbiology Spectrum

Abbreviated Title: Microbiol Spectr

Publisher: American Society for Microbiology

ISSN (Electronic): 2165-0497

Publication date Created: May 19 2017

Publication date (Print): May 19 2017

Volume: 5

Issue: 3

Affiliations

[1 ]Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, and Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21231-1002