Totally drug-resistant TB

One of the biggest problems in Tuberculosis (TB) therapy nowadays is that patients have to take antibiotics for up to 9 months. As many patients feel better before this time, they prematurely stop their treatment, leaving pools of the most drug-resistant M. tuberculosis in their lungs. This contributes to the emergence of complete drug resistance in future patients.

In the past few years, strains of drug-resistant Mtb have become prevalent. In fact, resistance is so widespread that it is now being classified as multi-drug resistant (MDR-TB) and extreme-drug resistant (XDR-TB). Two of the world’s most populous countries, India and China, account for more than 50% of the world’s MDR-TB cases.

Recent reports have also confirmed a new Mtb strain that is completely untreatable and has been designated as Totally drug resistance TB (TDR-TB). Indeed, strains of Mtb have even evolved resistance to all major available anti-TB drugs. India (2012) is the third country in which a total drug-resistant form of TB has emerged, following cases documented in Italy in 2007 and Iran in 2009. There is a need for a more readily available treatment that is effective against both sensitive and drug-resistant strains of M. tuberculosis is evident.

Mycobacteria and the great wall

The mycobacterial cell wall is unique, thick waxy, and hydrophobic, ensuring its survival inside human macrophages by resisting oxidative damages. The waxy, highly impermeable nature of the wall provides the required defense mechanism against antibiotic agents and the host organisms. A key component of the cell wall is mycolic acids. Mycolic acid accounts for up to 60% of the organisms' dry weight, which means that most percentage of mycobacteria is a cell wall. A thorough understanding of the influence of polarity on drug penetration into a highly impermeable mycobacterial cell wall will improve permeability.

The permeation ability of a lipophilic molecule is inversely related to the cell wall's fluidity, which decreases as the length of fatty acids in the mycolic acids layer increases. The permeability barrier presented by this cell envelope is also thought to be why many common antibiotics are ineffective against mycobacteria. Lipophilic drugs, such as fluoroquinolones or rifamycins, pass more quickly through the lipid-rich cell wall and thus are more active.

Depending on the library screens towards compounds with a particular physicochemical parameter could be detrimental and decrease the diversity in finding new anti-TB drugs.

Enoyl reductase: One target, Two major Global Threats

Tuberculosis and Malaria are two major global threats; both account for 5 million deaths annually (mostly in developing countries). Despite the worldwide ravages of Tuberculosis and Malaria, chemotherapeutic regimens against these two diseases have remained largely unchanged. There is an urgent need to develop novel, effective, and affordable drugs to treat both diseases because the resistance has developed or is developing to existing therapy. Scientists around the world are seeking new ways to combat the two opportunistic pathogens.

Mycobacterium tuberculosis and Plasmodium Falciparum are causative agents of tuberculosis and malaria, respectively. Both organisms share enzymatic components of the type II fatty acid biosynthetic pathway (FAS-II). Enoyl acyl carrier protein reductase (ENR) is one of the key type II enzymes, has been repeatedly validated as an effective antimicrobial target (e.g., INH, diazoborines, triclosan, and thiolactomycin).

Triclosan, the ENR inhibitor, showed excellent activity against both organisms. Targeting ENR  with a new class of compounds may yield new drugs against these devastating pathogens.

Naked Discovery

Unlike the highest secrecy in closed-door traditional drug discovery by the pool of rigid mindset scientists, the Open Source Drug Discovery (OSSD) Program aims to address the issue by capturing the youngest and brightest minds around the globe to be a part of developing drugs to treat diseases such as drug-resistant TB and malaria, and HIV. Open-source software may have been around for many years, but using an open-source model to speed up drug discovery is a relatively new idea

"Research labs in India are filled more with technicians, as opposed to creative minds. "You really don’t need to have a doctorate in pharmacy to contribute to developing a drug" said Samir Brahmachari, Director General of India’s Council of Scientific and Industrial Research (CSIR), and he believes that the OSDD can be as successful as Linux or a Wikipedia.

Tuberculosis kills at least 3,30,000 Indians annually and 1.7 million people Globally. The incidence of multi- and extensively drug-resistant strains of TB ( MRD- and XRD- TB ) demands renewed efforts to develop a novel class of fast-acting anti TB chemotherapeutics. Recently, Indian scientists have mapped the Mtb tuberculosis genome under the OSDD initiative of CSIR, giving hope of discovering new drugs for TB. This is the first time that the Mtb genome's comprehensive mapping has been accumulated, confirmed, and made available publicly.

This Connect to decode‘S (C2D) finding may contain critical data to unlock previously undiscovered details of TB, resulting in development opportunities for urgently needed new drugs in India and other developing countries.

Kill the Bugs, Selectively

“Today, we have tuberculosis drugs you have to take for nine months, why can’t we find one that works in three days” - Bill Gates. 

Tuberculosis (TB) is a chronic contagious disease caused by  Mycobacterium tuberculosis (M.tb), one of the leading causes of death worldwide. The WHO estimates about one-third of the world’s population is infected with M.tb, 10% of those infected will progress to active TB disease during their lifetime. The tuberculosis pandemic has been declared a global health emergency as the growing resistance of M.tb to Antibiotics coincides with the spread of risk factors such as HIV/AIDS and diabetes. TB is a complex disease. The current TB drug regimen, a product of scientific advances of the 1960s, requires six to nine months of treatment for active, drug-susceptible TB. Unfortunately, many patients do not or cannot complete this treatment. Poor adherence and prescribing practices have led to the emergence of multi- and extensively drug-resistant strains of TB (MDR-TB and XDR-TB) that increasingly defy current medicines and spread throughout many regions of the globe. The incidence of MRD- and XRD- TB demands renewed efforts to develop a novel class of fast-acting anti TB chemotherapeutics.

 

Mycobacterium tuberculosis is one of the few bacterial species with a proteasome. A team of scientists led by researchers from Weill Cornell Medical College  has found that some oxathiazolone compounds kill tuberculosis-causing bacteria by selectively inhibiting mycobacterial proteasomes without affecting human proteasomes. These compounds were showing no apparent toxicity to mammalian cells. The oxathiazolone compounds are the first example of an anti-tubercular agent that inhibits protein breakdown. The ability of brief exposure to oxathiazol-2-one compounds to inhibit M.tb proteasomes permanently makes it a potential target for anti-TB therapy. These  findings  may lead to drugs that destroy TB in the dormant stage of the lifecycle.