Unlocking Opportunities for and .

In the recent decade, scientific communities have toiled to tackle the emerging burden of drug-resistant tuberculosis (DR-TB) and rapidly growing opportunistic nontuberculous mycobacteria (NTM). Among these, two neglected mycobacteria species of the Acinetobacter family, and , are the etiological agents of leprosy and Buruli ulcer infections, respectively, and fall under the broad umbrella of neglected tropical diseases (NTDs). Unfortunately, lackluster drug discovery efforts have been made against these pathogenic bacteria in the recent decade, resulting in the discovery of only a few countable hits and majorly repurposing anti-TB drug candidates such as telacebec (Q203), P218, and TB47 for current therapeutic interventions.

Rationally Designed Novel Phenyloxazoline Synthase Inhibitors: Chemical Synthesis and Biological Evaluation to Accelerate the Discovery of New Antimycobacterial Antibiotics.

The uncontrolled spread of drug-resistant tuberculosis (DR-TB) clinical cases necessitates the urgent discovery of newer chemotypes with novel mechanisms of action. Here, we report the chemical synthesis of rationally designed novel transition-state analogues (TSAs) by targeting the cyclization (Cy) domain of phenyloxazoline synthase (MbtB), a key enzyme of the conditionally essential siderophore biosynthesis pathway. Following bio-assay-guided evaluation of TSA analogues preferentially in iron-deprived and iron-rich media to understand target preferentiality against a panel of pathogenic and non-pathogenic mycobacteria strains, we identified a hit, i.

Approaches for targeting the mycobactin biosynthesis pathway for novel anti-tubercular drug discovery: where we stand.

Introduction: Several decades of antitubercular drug discovery efforts have focused on novel antitubercular chemotherapies. However, recent efforts have greatly shifted toward countering extremely/multi/total drug-resistant species. Targeting the conditionally essential elements inside Mycobacterium is a relatively new approach against tuberculosis and has received lackluster attention.

Mycobactin Analogues with Excellent Pharmacokinetic Profile Demonstrate Potent Antitubercular Specific Activity and Exceptional Efflux Pump Inhibition.

In this study, we have designed and synthesized pyrazoline analogues that partially mimic the structure of mycobactin, to address the requirement of novel therapeutics to tackle the emerging global challenge of antimicrobial resistance (AMR). Our investigation resulted in the identification of novel lead compounds and as potential mycobactin biosynthesis inhibitors against mycobacteria. Moreover, candidates efficiently eradicated intracellularly surviving mycobacteria.

The Mycobactin Biosynthesis Pathway: A Prospective Therapeutic Target in the Battle against Tuberculosis.

The alarming rise in drug-resistant clinical cases of tuberculosis (TB) has necessitated the rapid development of newer chemotherapeutic agents with novel mechanisms of action. The mycobactin biosynthesis pathway, conserved only among the mycolata family of actinobacteria, a group of intracellularly surviving bacterial pathogens that includes , generates a salicyl-capped peptide mycobactin under iron-stress conditions in host macrophages to support the iron demands of the pathogen. This essentiality makes this less explored mycobactin biosynthesis pathway a promising endogenous target for novel lead-compounds discovery.

Scaffold Based Search on the Desferithiocin Archetype.

Iron overload disorder and diseases where iron mismanagement plays a crucial role require orally available iron chelators with favourable pharmacokinetic and toxicity profile. Desferrithiocin (DFT), a tridentate and orally available iron chelator has a favourable pharmacokinetic profile but its use has been clinically restricted due to its nephrotoxic potential. The chemical architecture of the DFT has been naturally well optimized for better iron chelation and iron clearance from human biological system.