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Background <p>Rifampicin-resistant <i>Mycobacterium tuberculosis</i> (RR-TB) and methicillin-resistant <i>Staphylococcus</i> aureus (MRSA) underscore the need for new antibacterial chemotypes active across <i>M. tuberculosis </i><i>M. tuberculosis</i> and Gram-positive pathogens. Both thiourea and tetrazole are well-established scaffolds in the scientific community for their promising antibacterial properties. The combination of tetrazole and thiourea moieties into a single molecular framework presents a promising strategy to overcome antimicrobial resistance.</p> Methods <p>We designed and synthesized a series of tetrazole–thiourea derivatives (<b>1</b>–<b>9</b>) and a bis-tetrazole hybrid (<b>10</b>) through a one-step synthetic approach. Their antimicrobial potential was evaluated using a combination of <i>in silico</i> absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions, experimental lipophilicity determination (logD), and in vitro antibacterial assays against both reference and multidrug-resistant staphylococcal strains. Additionally, antitubercular activity was assessed against drug-sensitive, multidrug-resistant (MDR), and extensively drug-resistant (XDR) <i>M. tuberculosis</i> isolates. Molecular docking studies were performed to explore the binding interactions of the compounds with dihydrofolate reductase (DHFR) and penicillin-binding protein 4 (PBP4).</p> Results <p>Compound <b>2</b>, bearing a trifluoromethyl substituent, was the most potent. It achieved sub-µg/mL minimum inhibitory concentrations (MICs, 0.1–0.5 µg/mL) against staphylococci, comparable to ciprofloxacin, and maintained strong antitubercular activity (MIC = 0.5 µg/mL) across drug-sensitive, MDR, and XDR strains. Docking supported a dual-target mechanism involving DHFR and PBP4, providing a plausible rationale for its broad antibacterial efficacy. Despite higher lipophilicity within the series, compound <b>2</b> showed favorable ADMET predictions and experimental logD values in the developable range.</p> Conclusions <p>The tetrazole–thiourea scaffold, exemplified by compound <b>2</b>, delivers dual efficacy against multidrug-resistant staphylococci and <i>M. tuberculosis</i>. These findings position compound <b>2</b> as a promising lead and a rational starting point for hit-to-lead optimization focused on potency–permeability balance and experimental confirmation of dual-target engagement.</p> Graphical Abstract <p></p>

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Discovery of a tetrazole-thiourea derivative as a potential active agent against multidrug-resistant Staphylococcus aureus and Mycobacterium tuberculosis

  • 期刊论文

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  • 发表日期：

    2026年3月19日

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  • Jolanta Szymańska-Majchrzak,
  • Agnieszka Głogowska,
  • Ewa Augustynowicz-Kopeć,
  • Katarzyna Ewa Greber,
  • Krzesimir Ciura,
  • Wioletta Olejarz,
  • Tomasz Szostek,
  • Marta Struga,
  • Daniel Szulczyk

摘要

Background

Rifampicin-resistant Mycobacterium tuberculosis (RR-TB) and methicillin-resistant Staphylococcus aureus (MRSA) underscore the need for new antibacterial chemotypes active across M. tuberculosis M. tuberculosis and Gram-positive pathogens. Both thiourea and tetrazole are well-established scaffolds in the scientific community for their promising antibacterial properties. The combination of tetrazole and thiourea moieties into a single molecular framework presents a promising strategy to overcome antimicrobial resistance.

Methods

We designed and synthesized a series of tetrazole–thiourea derivatives (1–9) and a bis-tetrazole hybrid (10) through a one-step synthetic approach. Their antimicrobial potential was evaluated using a combination of in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions, experimental lipophilicity determination (logD), and in vitro antibacterial assays against both reference and multidrug-resistant staphylococcal strains. Additionally, antitubercular activity was assessed against drug-sensitive, multidrug-resistant (MDR), and extensively drug-resistant (XDR) M. tuberculosis isolates. Molecular docking studies were performed to explore the binding interactions of the compounds with dihydrofolate reductase (DHFR) and penicillin-binding protein 4 (PBP4).

Results

Compound 2, bearing a trifluoromethyl substituent, was the most potent. It achieved sub-µg/mL minimum inhibitory concentrations (MICs, 0.1–0.5 µg/mL) against staphylococci, comparable to ciprofloxacin, and maintained strong antitubercular activity (MIC = 0.5 µg/mL) across drug-sensitive, MDR, and XDR strains. Docking supported a dual-target mechanism involving DHFR and PBP4, providing a plausible rationale for its broad antibacterial efficacy. Despite higher lipophilicity within the series, compound 2 showed favorable ADMET predictions and experimental logD values in the developable range.

Conclusions

The tetrazole–thiourea scaffold, exemplified by compound 2, delivers dual efficacy against multidrug-resistant staphylococci and M. tuberculosis. These findings position compound 2 as a promising lead and a rational starting point for hit-to-lead optimization focused on potency–permeability balance and experimental confirmation of dual-target engagement.

Graphical Abstract