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Antibiotic resistance is a major public health concern that arises when bacteria evolve mechanisms to withstand the effects of antibiotic treatments. This resistance can be intrinsic, acquired through genetic mutations, or transferred between bacteria via horizontal gene transfer. The development of antibiotic resistance poses significant challenges in treating bacterial infections and necessitates ongoing research to develop new therapeutic strategies.Intrinsic resistance occurs when bacterial...
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The bacterial cell wall is an essential structural component that encases the plasma membrane, preserving cellular integrity, determining shape, and protecting against osmotic stress. This rigid yet flexible structure primarily comprises peptidoglycan, a polymer that forms a mesh-like matrix conferring mechanical strength and flexibility.Peptidoglycan Composition and StructurePeptidoglycan, the core of the bacterial cell wall, comprises alternating units of N-acetylglucosamine (NAG) and...
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Related Experiment Video

Updated: Dec 19, 2025

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A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance.

James K Martin1, Joseph P Sheehan1, Benjamin P Bratton2

  • 1Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.

Cell
|June 5, 2020
PubMed
Summary

A novel compound, SCH-79797, targets two bacterial pathways simultaneously, offering a potent strategy against antibiotic-resistant Gram-negative and Gram-positive bacteria with low resistance development. Its derivative, Irresistin-16, shows efficacy in preclinical models.

Keywords:
Acinetobacter baumanniiGram-negative pathogensNeisseria gonorrhoeaeantibioticsbroad spectrumdual-target drugsfolate metabolismmembrane disrupting

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Area of Science:

  • Microbiology
  • Drug Discovery
  • Antimicrobial Resistance

Background:

  • Antibiotic resistance poses a global health crisis, with a critical lack of new drugs targeting Gram-negative bacteria.
  • Existing treatments are becoming less effective against resistant strains like methicillin-resistant Staphylococcus aureus (MRSA).

Purpose of the Study:

  • To characterize a novel compound, SCH-79797, with a dual-targeting mechanism of action (MoA) against resistant bacteria.
  • To develop and evaluate a more potent derivative, Irresistin-16, for treating challenging bacterial infections.

Main Methods:

  • Utilized a pipeline of quantitative imaging, proteomics, genetics, metabolomics, and cell-based assays to elucidate the MoA of SCH-79797.
  • Tested SCH-79797 and its derivative Irresistin-16 against Gram-negative and Gram-positive bacteria, including MRSA and Neisseria gonorrhoeae.
  • Employed a mouse vaginal infection model to assess the in vivo efficacy of Irresistin-16.

Main Results:

  • SCH-79797 exhibits a unique dual MoA, targeting both folate metabolism and bacterial membrane integrity.
  • The compound demonstrated undetectably low resistance frequencies and outperformed combination therapies against MRSA persisters.
  • Irresistin-16 showed enhanced potency and efficacy against Neisseria gonorrhoeae in a preclinical mouse model.

Conclusions:

  • Combining multiple MoAs onto a single molecule is a promising strategy for developing new antibiotics against difficult-to-treat pathogens.
  • SCH-79797 and Irresistin-16 represent promising leads for novel antibacterial therapies to combat the rising threat of antibiotic resistance.