Development and evaluation of novel anti-tuberculosis drug molecules

Abstract

Bacterial infections have become a major problem for humanity. Among these, tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) continues to be one of the leading causes of death around the world. Due to the evolution of Mtb, it has developed unique mechanisms to reside inside macrophages and induce persistent infections. In this chemotherapy era, many anti-TB drugs have been discovered; however, with the rise in multidrug-resistant (MDR) strains the therapeutic efficacy of the drugs is minimized. Several new medications are currently being tested, however many of them fail in clinical trials due to non-targeted therapy, long regimen durations, and multiple adverse effects. As drug-resistant TB is a major public health concern, finding an effective way to deliver drugs to the target site is important. Researchers are looking for a promising way to safely deliver the drugs to the infected site as well as to boost the treatment efficacy by combining current antibiotics with metal complexes such as nanoparticles (NP). Despite their benefits, such as immunomodulatory effects and strong antibacterial activity, certain NPs are hazardous, limiting their usefulness as a delivery platform. As a result, there is a great desire for an alternative that can operate as a vehicle for anti-TB drug delivery. Due to several promising qualities such as high porosity, wide surface area, high drug loading capacity, and higher encapsulation efficiency, a novel class of material known as "metal organic framework (MOF)" is receiving interest. Thus, it could act as a drug delivery vehicle to deliver anti-TB drugs. To study more on the efficacy and biocompatibility of MOFs, in this study, the synthesis of Cu-MOFs and the encapsulation of one of the potent 1st line anti-TB drugs, isoniazid (INH) was carried out (i.e., INH@CuMOF). Characterization of INH@Cu-MOF confirmed the encapsulation of INH into Cu-MOFs and demonstrated the compound is thermally stable. In vitro experiments revealed that INH@Cu-MOF has anti-mycobacterial activity with no cytotoxicity for RAW 264.7 macrophages. INH@CuMOF also demonstrated less biofilm-forming and more biofilm-disrupting ability. Thus, our study suggests Cu MOFs can be a potential drug delivery vehicle to sustainably deliver INH for the treatment of TB. Further, as M.tb strains have developed several mechanisms to evade standard anti-TB treatment, it necessitates the development of novel anti-TB drugs. Drug repurposing is one of many other methods that can be tested to combat MDR TB infections. As the traditional drug development process is known to be costly as well as time-consuming thus, we performed the in-silico structural as well as functional characterization of mycobacterial cell wall protein to understand its functionality and determine any previously known drug that can be repurposed for the treatment of TB. It was followed by structure based virtual screening to discover potentially novel or repurposed anti-TB drugs.