In Search of New Cures for Tuberculosis

Protopopova, Marina; Bogatcheva, Elena; Никоненко, Б. В.; Hundert, Sam; Einck, Leo; Nacy, Carol A.

doi:10.2174/157340607780620626

Cited by 48 publications

(26 citation statements)

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“…The novel TB drugs currently in clinical trials were not discovered through target-based cell screening but through either whole-cell phenotypic screening (TMC207 [1]) or chemical modification of previous hits (PA-824 [35], SQ109 [12], and OPC-67683 [28]). The advantage of target-based chemical library screening is that the target of the identified inhibitors is known, which means that the mode of action and mode of resistance can be easily identified.…”

Section: Discussionmentioning

confidence: 99%

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

Vilchèze

Baughn

Tufariello

et al. 2011

Antimicrob Agents Chemother

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Drug resistance in Mycobacterium tuberculosis has become a serious global health threat, which is now complicated by the emergence of extensively drug-resistant strains. New drugs that are active against drugresistant tuberculosis (TB) are needed. We chose to search for new inhibitors of the enoyl-acyl carrier protein (ACP) reductase InhA, the target of the first-line TB drug isoniazid (also known as isonicotinoic acid hydrazide [INH]). A subset of a chemical library, composed of 300 compounds inhibiting Plasmodium falciparum enoyl reductase, was tested against M. tuberculosis. Four compounds were found to inhibit M. tuberculosis growth with MICs ranging from 1 M to 10 M. Testing of these compounds against M. tuberculosis in vitro revealed that only two compounds (CD39 and CD117) were bactericidal against drug-susceptible and drug-resistant M. tuberculosis. These two compounds were also bactericidal against M. tuberculosis incubated under anaerobic conditions. Furthermore, CD39 and CD117 exhibited increased bactericidal activity when used in combination with INH or rifampin, but CD39 was shown to be toxic to eukaryotic cells. The compounds inhibit InhA as well the fatty acid synthase type I, and CD117 was found to also inhibit tuberculostearic acid synthesis. This study provides the TB drug development community with two chemical scaffolds that are suitable for structureactivity relationship study to improve on their cytotoxicities and bactericidal activities in vitro and in vivo.The fight against tuberculosis (TB), a disease caused by the bacillus Mycobacterium tuberculosis, is facing new challenges with the surge of multidrug-resistant (MDR) TB and the recent emergence of extensively drug-resistant (XDR) TB (8). TB strains resistant to the first-line anti-TB drugs (FLDs) isoniazid (also known as isonicotinoic acid hydrazide [INH]) and rifampin (RIF) are classified as MDR-TB, while XDR-TB is defined as MDR-TB resistant to any fluoroquinolone and one or more of the three injectable drugs (6). The need for novel TB drugs has spurred a new interest in TB drug development, and several new TB drugs are currently being tested in clinical trials (18). Nevertheless, expanding the pharmacopeia of active TB drugs remains an important goal, as M. tuberculosis has proven to be more than adept at acquiring drug resistance. One strategy to develop new drugs effective against MDR-and XDR-TB is to target essential functions that are not aims of the current anti-TB drug regimen. An alternative is to develop new drugs with novel requirements for inhibition of a bona fide target, with the goal of circumventing extant drug resistance.TB is resistant to most commonly used antibacterial agents due in part to its unusual cell wall structure. The mycobacterial cell wall contains unique long-chain (C 70 to C 90 ), ␣-alkyl, ␤-hydroxy fatty acids called mycolic acids. The synthesis of these fatty acids requires the coenzyme A (CoA)-dependent fatty acid synthase type I (FASI) and the acyl carrier protein (ACP)-dependent multienzyme fatty ...

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Section: Discussionmentioning

confidence: 99%

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

Vilchèze

Baughn

Tufariello

et al. 2011

Antimicrob Agents Chemother

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“…LL3858 is being investigated in phase I clinical trials (5,71). A fixed-dose combination called LL3848, containing LL3858 and the standard, first-line anti-TB drugs, is also being developed (126).…”

Section: Ii) Gatifloxacin (A) Mechanism Of Actionmentioning

confidence: 99%

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

Boogaard

Kibiki

Kisanga

et al. 2009

Antimicrob Agents Chemother

216

132

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2One-third of the world population is infected with Mycobacterium tuberculosis (MTB) and hence at risk of developing active tuberculosis (TB). Each year, 8.8 million patients are newly diagnosed with active TB and 1.6 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of TB patients are HIV positive (176). The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings). PROBLEMS WITH CURRENT TUBERCULOSIS TREATMENTThere are several major problems associated with the currently available TB treatment. First, the duration and complexity of treatment result in nonadherence to treatment. This leads to suboptimal response (failure and relapse), the emergence of resistance, and continuous spread of the disease (168). Second, adverse events in response to anti-TB drugs are common and contribute to the problem of nonadherence (19,168). Third, the increasing incidence of multidrug-resistant (MDR; resistance to at least rifampin and isoniazid) and extensively drug-resistant (XDR; MDR resistance plus resistance to a fluoroquinolone and an aminoglycoside) TB is a serious concern. Resistant TB occurs in the presence of partially suppressive drug concentrations that enable replication of bacteria, the formation of mutants, and overgrowth of wild-type strains by mutants (selective pressure) (175). The prevalence of MDR TB in new TB cases ranged from 0% in some Western European countries to more than 22% in Azerbaijan (2002 to 2007 survey); 14 of 72 participating countries reported an MDR TB prevalence of more than 5% (177). Second-line drugs for drug-resistant TB are not available everywhere and are less effective, more toxic, and require longer use than first-line drugs (61). Fourth, coinfection of TB and HIV is a problem by itself. Combined treatment of TB and HIV involves a high pill count with associated adherence problems, overlapping toxicity profiles of the antiretroviral and anti-TB drugs, drug interactions between rifampin and the antiretroviral protease inhibitors, and the risk of immune reconstitution syndrome (104). Fifth, prophylactic therapy of latent TB (TB infection without symptoms) with isoniazid is also associated with problems of nonadherence (180). Attempts to shorten treatment with alternative drugs resulted in severe adverse events (64,150,155).The World Health Organization (WHO) has developed the directly observed therapy short course (DOTS) strategy to optimize response and adherence to TB treatment. However, DOTS is labor-intensive and expensive. It causes a high burden on public health programs, especially in developing countries with limited human resources (49). In addition, TB diagnosis in the DOTS strategy is based on sputum microscopy, rather than sputum culture (173). Only advanced pulmonary TB is detected by sputum...

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“…This, in turn, will require an advance in our knowledge of the disease and the biology of M. tuberculosis as well as the application of innovative new approaches and technologies. Much progress has been made in the past decade, and a number of new tools are under development (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). However, much more needs to be done.…”

Section: Introductionmentioning

confidence: 99%