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Identification of Chemical Scaffolds Targeting Drug-Resistant and Latent Mycobacterium tuberculosis through High-Throughput Whole-Cell Screening.
Perveen, Summaya; Negi, Anjali; Saini, Sapna; Gangwar, Anjali; Sharma, Rashmi.
Affiliation
  • Perveen S; Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180001, India.
  • Negi A; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
  • Saini S; Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180001, India.
  • Gangwar A; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
  • Sharma R; Infectious Diseases Division, CSIR- Indian Institute of Integrative Medicine, Jammu 180001, India.
ACS Infect Dis ; 10(2): 513-526, 2024 02 09.
Article in En | MEDLINE | ID: mdl-38238154
ABSTRACT
Identification of structurally unique chemical entities targeting unexplored bacterial targets is a prerequisite to combat increasing drug resistance against Mycobacterium tuberculosis. This study employed a whole-cell screening approach as an initial filter to scrutinize a 10,000-compound chemical library, resulting in the discovery of seven potent compounds with MIC values ranging from 1.56 to 25 µM. These compounds were categorized into four distinct chemical groups. Remarkably, they demonstrated efficacy against drug-resistant and nonreplicating tuberculosis strains, highlighting their effectiveness across different infection states. With a favorable selectivity index (>10), these compounds showed a safe therapeutic range and exhibited potency in an intracellular model of Mtb infection, mimicking the in vivo setup. Combining these identified hits with established anti-TB drugs revealed additive effects with rifampicin, isoniazid, and bedaquiline. Notably, IIIM-IDD-01 exhibited synergy with isoniazid and bedaquiline, likely due to their complementary mechanisms of targeting Mtb. Most potent hits, IIIM-IDD-01 and IIIM-IDD-02, displayed time- and concentration-dependent killing of Mtb. Mechanistic insights were sought through SEM and docking studies, although comprehensive evaluation is ongoing to unravel the hits' specific targets and modes of action. The hits demonstrated favorable pharmacokinetic properties (ADME-Tox) and showed a low risk of adverse effects, along with a predicted high level of oral bioavailability. These promising hits can serve as an initial basis for subsequent medicinal chemistry endeavors aimed at developing a new series of anti-TB agents. Moreover, the study affirms the significance of high-throughput in vitro assays for the TB drug discovery. It also emphasizes the necessity of targeting diverse TB strains to address the heterogeneity of tuberculosis bacteria.
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Full text: 1 Collection: 01-internacional Health context: 2_ODS3 / 3_ND Database: MEDLINE Main subject: Tuberculosis / Latent Tuberculosis / Mycobacterium tuberculosis Type of study: Diagnostic_studies / Prognostic_studies / Screening_studies Limits: Humans Language: En Journal: ACS Infect Dis Year: 2024 Document type: Article

Full text: 1 Collection: 01-internacional Health context: 2_ODS3 / 3_ND Database: MEDLINE Main subject: Tuberculosis / Latent Tuberculosis / Mycobacterium tuberculosis Type of study: Diagnostic_studies / Prognostic_studies / Screening_studies Limits: Humans Language: En Journal: ACS Infect Dis Year: 2024 Document type: Article