griselimycin and Tuberculosis--Multidrug-Resistant

According to WHO report, globally about 10 million active tuberculosis cases, resulting in about 1.6 million deaths, further aggravated by drug-resistant tuberculosis and/or comorbidities with HIV and diabetes are present. Incomplete therapeutic regimen, meager dosing, and the capability of the latent and/or active state tubercular bacilli to abide and do survive against contemporary first-line and second line antitubercular drugs escalate the prevalence of drug-resistant tuberculosis. As a better understanding of tuberculosis, microanatomy has discovered an extended range of new promising antitubercular targets and diagnostic biomarkers. However, there are still no new approved antitubercular drugs of routine therapy for several decades, except for bedaquiline, delamanid, and pretomanid approved tentatively. Despite this, innovative methods are also urgently needed to find potential new antitubercular drug candidates, which potentially decimate both latent state and active state

Topics: Animals; Antitubercular Agents; Coumarins; Drug Design; Humans; Isoniazid; Mycobacterium tuberculosis; Peptides, Cyclic; Pharmaceutical Preparations; Pore Forming Cytotoxic Proteins; Tuberculosis, Multidrug-Resistant

The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.

Topics: Animals; Antitubercular Agents; Bacterial Proteins; Cell Line, Tumor; Crystallography, X-Ray; Disease Models, Animal; DNA-Directed DNA Polymerase; Drug Design; Humans; Mice; Microbial Sensitivity Tests; Molecular Sequence Data; Molecular Targeted Therapy; Mycobacterium smegmatis; Mycobacterium tuberculosis; Peptides, Cyclic; Protein Structure, Secondary; Streptomyces; Tuberculosis, Multidrug-Resistant