2. Academic Validation
  3. Drug repurposing: antimicrobial and antibiofilm effects of MLS0315771 against Gram-positive bacteria

Drug repurposing: antimicrobial and antibiofilm effects of MLS0315771 against Gram-positive bacteria

  • BMC Microbiol. 2026 Apr 29;26(1):557. doi: 10.1186/s12866-026-05074-9.
Zhichao Xu # 1 2,  Yuanyuan Tang # 1 2,  Junhua Ma # 2,  Peiyu Li # 2,  Zewen Wen 2,  Zhijian Yu 2,  Bing Bai 3,  Zhong Chen 4,  Shiqing Han 5,  Tieying Hou 6
Affiliations

Affiliations

  • 1 College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, China.
  • 2 Department of Infectious Diseases, Shenzhen Key Laboratory for Endogenous Infections, Shenzhen Nanshan People's Hospital, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518052, China.
  • 3 Department of Infectious Diseases, Shenzhen Key Laboratory for Endogenous Infections, Shenzhen Nanshan People's Hospital, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518052, China. [email protected].
  • 4 Department of Infectious Diseases, Shenzhen Key Laboratory for Endogenous Infections, Shenzhen Nanshan People's Hospital, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518052, China. [email protected].
  • 5 College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211816, China. [email protected].
  • 6 Department of Infectious Diseases, Shenzhen Key Laboratory for Endogenous Infections, Shenzhen Nanshan People's Hospital, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518052, China. [email protected].
  • # Contributed equally.
PMID: 42056861 DOI: 10.1186/s12866-026-05074-9
Abstract

The escalating prevalence of multidrug-resistant (MDR) and biofilm-forming Staphylococcus aureus has created an urgent demand for alternative therapeutic strategies beyond conventional Antibiotics. In this study, we report for the first time the notable Antibacterial and antibiofilm activities of MLS0315771, a competitive phosphomannose isomerase (MPI) inhibitor, against a broad range of Gram-positive bacteria. MLS0315771 exhibited notable inhibitory and bactericidal effects against Staphylococcus aureus and Enterococcus faecium. The MIC₅₀/MIC₉₀ values were 25/25 µM for MSSA, 12.5/12.5 µM for MRSA, and 6.25/6.25 µM for linezolid-resistant E. faecium. This compound also significantly delayed Bacterial proliferation at subinhibitory concentrations and reduced mature biofilms in vitro. Time-kill assays revealed that MLS0315771 displayed time-dependent bactericidal activity comparable or superior to vancomycin. Proteomic profiling of S. aureus exposed to MLS0315771 and functional assays confirmed that MLS0315771 disrupts Bacterial membrane integrity and induces depolarization, thereby impairing essential membrane functions. Checkerboard analyses further indicated that unsaturated long-chain fatty acids antagonized its Antibacterial activity, supporting a membrane-targeting Antibacterial mechanism. Moreover, MLS0315771 displayed low hemolytic activity and moderate, cell line-dependent cytotoxicity toward mammalian cells, suggesting a limited but measurable therapeutic window. Collectively, these findings demonstrate that MLS0315771 acts as a novel membrane-targeting Antibacterial agent with notable Antibacterial activity against MDR and biofilm-forming Gram-positive pathogens, highlighting its potential as a candidate lead compound for future antimicrobial development.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12866-026-05074-9.

Keywords

Staphylococcus aureus; Biofilm inhibition; MLS0315771; Membrane-targeting antibacterial agent; Multidrug resistance.

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