The impact of genomics on the search for novel tuberculosis drugs

Ken Duncan

Glaxo Wellcome Research and Development, Medicines Research Centre, Gunnels Wood ~Road, Stevenage, Hertfordshire SG1 2NY, UK

Abstract.The emergence of multidrug-resistant strains of Mycobacterium tuberculosis has highlighted the need for new drugs to treat tuberculosis. Drugs that either shorten the overall duration of therapy or that simplify the regimen would significantly improve compliance and hence reduce treatment failure rates. The drug development process begins with identification and validation of specific targets. These may be relevant for inhibiting growth of the bacterium in vitro, and hence yield novel bactericidal agents, or they may be required at other stages of growth, such as survival in host macrophages. With the availability of the complete genome sequence of M. tuberculosis, the primary sequence of every drug target in the pathogen is known. A combination of approaches is being employed to exploit the information contained in the genome and thereafter to identify lead compounds that may yield new drugs.

1998 Genetics and tuberculosis. Wiley, Chichester (Novartis Foundation Symposium 217) p228-238

The chemotherapeutic era of tuberculosis treatment began in 1944 with the discovery of streptomycin by Selman Waksman and his colleagues. Isoniazid, the agent with the most potent activity known against the tubercle bacillus, Mycobacterium tuberculosis, was introduced in 1952. The finding that the broad-spectrum antibacterial agent rifamycin has activity against M. tuberculosis revolutionized treatment of tuberculosis with the subsequent development of the short-course (albeit six-month) multidrug regimen in use today. This regimen can achieve cure rates of > 95% when used correctly. Despite the wide availability of these relatively inexpensive drugs, the number of tuberculosis sufferers continues to rise worldwide, prompting the World Health Organization (WHO) to declare tuberculosis 'a global emergency' in 1993.

The drawbacks of the multidrug regimen are obvious. The number of tablets, their toxic side-effects and the long duration of the therapy lead to poor compliance. Inevitably, this results in a significant rate of treatment failure and, worse, selection of resistant organisms. In a recent global survey, drug-resistant tuberculosis was found in every country that reported data, with a median level of 10.4% primary resistance, and 'hot spots' where resistance as high as 41% was identified (World Health Organization 1997a). Patients with multidrug-resistant tuberculosis are difficult to treat and continue to infect others with the resistant bacteria. In order to overcome the limitations in current therapy, the WHO recommends the implementation of a programme called directly observed therapy, short-course, or DOTS (World Health Organization 1997b). New chemotherapeutic agents with activity against multidrug-resistant tuberculosis and drugs that can provide a shorter and simpler regimen are needed.

Since the 1960s, there has been relatively little progress in tuberculosis drug development. Semi-synthetic rifamycin derivatives such as rifabutin and rifapentine (Baohong et al 1993) have not yet achieved widespread clinical use. The experimental benzoxazinorifamycin, KRM-1648 (Fig. 1), also shows promise (Saito et al 1991, Klemens et al 1994a), but such agents represent incremental steps in therapy improvement. Although they have some advantages over parent rifampicin, such as a longer half-life in humans which may permit intermittent chemotherapy, there are disadvantages of this approach. In particular, overcoming existing resistance mechanisms to the entire class of compounds can be an insurmountable challenge.

New broad-spectrum antibacterial agents that have particularly good activity against M. tuberculosis are also being used in the fight against tuberculosis (Fig. 1). The quinolone levofloxacin (Klemens et al 1994b) is already being used in the clinic and the oxazolidinone U-100480 has good in vitro and in vivo activity (Barbachyn et al 1996).

Researchers at PathoGenesis Corporation have described a series of nitroimidazopyrans, exemplified by PA-824 (Fig. 1), with potent selective antimycobacterial activity. They have no cross-resistance with other antibiotics and work via a novel, as yet uncharacterized mechanism (W. R. Baker, E. L. Keeler, S. Cai, J. A. Towell, D. R. Pastor, J. N. Morgenroth, S. W. Anderson & T. M. Arain, unpublished paper, Interscience Conference on Antimicrobial Agents and Chemotherapy, 15—18 September 1996).

Immunotherapeutic approaches are described in detail elsewhere in this symposium (this volume: Johnson et al 1998, Rook & Hernandez-Pando 1998).

Over 95% of tuberculosis sufferers are in the developing world. The drugs available today can achieve high cure rates. M. tuberculosis is a slow-growing, airborne pathogen that requires specialized handling facilities and the available models of infection are lengthy and difficult. Together, these factors make developing a new tuberculosis drug a daunting challenge. In this chapter the factors that influence the direction of a tuberculosis drug development programme are discussed. The availability of the M. tuberculosis genome sequence adds a new dimension to our knowledge ofthis important pathogen, and provides

KRM-1648

FIG. 1. Structure of potential new tuberculosis drugs.

greater opportunity than ever before for the rapid identification and validation of novel drug targets.

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