The development of anti-tuberculosis (TB) compounds from natural sources is reviewed.
A number of natural product-derived candidates have entered late-stage development.
Drug leads with novel modes of action is required to combat the alarming increase in drug-resistant TB cases.
Tuberculosis (TB) continues to be a significant cause of mortality and morbidity worldwide. An estimated 2 billion individuals are infected with Mycobacterium tuberculosis and annually there are approximately 10 million new cases of clinical TB and 1.5 million deaths. Currently available drugs and vaccines have had no significant impact on TB control. In addition, the emergence of drug resistant TB is considered a public health crisis, with some strains now resistant to all available drugs. Unfortunately, the growing burden of antibiotic resistance is coupled with decreased effort in the development of new antibiotics. Natural sources are attractive starting points in the search for anti-tubercular drugs because they are extremely rich in chemical diversity and have privileged antimicrobial activity. This review will discuss recent advances in the development of TB drug leads from natural products, with a particular focus on anti-mycobacterial compounds in late-stage preclinical and clinical development.
Emergent drug-resistant tuberculosis
The spread of drug resistant TB is a major threat to global TB control. These strains are now entrenched in most countries and are spreading at an alarming rate. Multi-drug resistant (MDR) TB isolates are resistant to isoniazid (INH) and rifampicin, the two frontline drugs for TB treatment, and have been detected in every country surveyed. In 2015 there were an estimated 480,000 new cases of MDR-TB, however only 50% of patients on MDR-TB treatment were successfully treated.1 This means hundreds of thousands of people worldwide are going untreated and continuing to spread drug resistant forms of the disease. Extensively drug-resistant (XDR) TB strains, first detected in 2006, are resistant to front-line and second-line anti-tubercular antibiotics. XDR-TB is now present in over 100 countries and represents approximately 10% of MDR-TB cases.1 Delayed diagnosis and inappropriate treatment leads to multiplication of resistance; this is best highlighted by the alarming emergence of totally drug resistant (TDR) TB, which is essentially untreatable using current drugs.2 In addition, TB treatment is long; standard treatment for drug sensitive strains is 6 to 12 months, while patients with drug resistant TB must endure a longer course of treatment (24 months or longer) with harsh side effects, high cost and a low chance of cure. The combination of long treatment and side effects results in poor compliance, which is a major contributor to the development of resistance. Thus it is evident that current methods of treatment and control for TB are not sustainable in the face of highly drug resistant TB; there is an obvious and urgent need for the development of new TB drugs that are effective against drug resistant M. tuberculosis strains, as well as strategies to reduce duration of treatment regimens.
Natural products as new treatments for TB
The search for new anti-TB agents has been slow; the last major anti-TB drug to be licensed for human use was rifampicin in 1963. Since that time a handful of compounds have entered human trials, and encouragingly two compounds, bedaquiline and delamanid, have recently received fast-tracked approval for use against MDR-TB.3However both drugs are associated with side-effects and are only recommended for those without other treatment options. Considering the restrictions on bedaquiline use, and the fact that XDR and TDR strains cannot be adequately treated with currently available antibiotics, many more compounds must enter the TB drug development ‘pipeline’ in order to adequately combat the TB problem. New anti-TB compounds must overcome the issues with current treatments (Table 1). The ideal anti-TB drug must display high potency, particularly against drug-resistant strains, and possess an adequate safety profile. In addition drugs should be active against latent and replicating forms of M. tuberculosis and have limited drug/drug interactions, particularly with anti-retroviral agents.
Problem with existing therapy Desired characteristics of new drugs Lengthy treatment Increased capacity to inhibit bacterial growth and shorten treatment time (e.g. <4 month). High pill burden Lower the number of pills and frequency of doses by using highly potent and bioavailable drugs. Also aim for intermittent treatment. Expensive Cheap to make and easily available to the developing world. Side effects Less toxic drugs. Intermittent treatment. Interaction with other drug Minimal drug-drug interaction with anti-virals, diabetes and non-TB drugs. Drug resistant M. tuberculosis strains Novel drugs with new mechanism of action. Lack of efficacy against latent TB Active against non-replicating bacteria and work effectively in hypoxic conditions. Drugs that can penetrate granulomas.