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Tridecaptin M, a New Variant Discovered in Mud Bacterium, Shows Activity against Colistin- and Extremely

Manoj Jangra1, Manpreet Kaur1, Rushikesh Tambat1

  • 1Clinical Microbiology and Bioactive Screening Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India.

Antimicrobial Agents and Chemotherapy
|April 3, 2019
PubMed

Insights

A new antibiotic, tridecaptin M, shows potent activity against critical Gram-negative superbugs resistant to last-resort drugs like colistin. It offers a novel mechanism by blocking bacterial ATP synthesis with low toxicity, addressing urgent treatment needs.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Drug Discovery

Background:

  • Gram-negative superbugs are critical priority pathogens due to antibiotic resistance.
  • Existing last-resort antibiotics like colistin are losing efficacy against extensively drug-resistant and pan-drug-resistant Enterobacteriaceae.
  • There is an urgent need for novel therapeutic strategies to combat multidrug-resistant bacterial infections.

Purpose of the Study:

  • To report the discovery of tridecaptin M, a novel antibiotic.
  • To evaluate the efficacy of tridecaptin M against colistin-resistant Enterobacteriaceae in vitro and in vivo.
  • To investigate the mechanism of action, cytotoxicity, and safety profile of tridecaptin M.

Main Methods:

  • Antibacterial activity was assessed using minimum inhibitory concentrations (MICs) against clinical strains.
  • Mode-of-action studies employed fluorescent probes to analyze membrane permeability and proton motive force.
  • Cytotoxicity and hemolytic activity were evaluated in cell lines, and in vivo toxicity was assessed in mice.
  • Efficacy was tested in a murine thigh infection model.

Main Results:

  • Tridecaptin M demonstrated potent activity (MICs 2-8 μg/mL) against colistin-resistant Klebsiella pneumoniae and mcr-1-positive Escherichia coli.
  • Unlike polymyxins, tridecaptin M inhibits bacterial ATP synthesis by dissipating proton motive force, without outer or cytoplasmic membrane permeabilization.
  • The compound exhibited negligible acquired resistance, low in vitro cytotoxicity and hemolytic activity, and no significant acute toxicity in mice.
  • Promising efficacy was observed in a mouse model of colistin-resistant K. pneumoniae thigh infection.

Conclusions:

  • Tridecaptin M represents a promising new class of antibiotics effective against challenging Gram-negative superbugs.
  • Its novel mechanism of action and favorable safety profile offer a potential solution to circumvent colistin resistance.
  • Natural products remain a vital resource for antibiotic discovery to address the critical unmet medical need for new therapies.
Keywords:
Gram-negative bacteriaPaenibacillus sp.XDR Enterobacteriaceaeantibacterial drug screeningantibiotic resistanceantimicrobial agentscolistin resistancenonribosomal peptidestridecaptin M

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