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Optimized LL-37-Derived Peptides Exhibit Antitubercular Activity, Induce Membrane Disruption, and P-Type ATPase

Paola A Santos1,2, Milena Maya-Hoyos1, Luz Mary Salazar1

  • 1Bioquímica y Biología Molecular de las Micobacterias-BBMM, Departamento de Química, Facultad de Ciencias, Universidad Nacional de Colombia, Carrera 30 N° 45-03, Bogotá 111321, Colombia.

Biomolecules
|May 27, 2026
PubMed

Insights

Optimized antimicrobial peptides derived from LL-37 show potent activity against tuberculosis (TB) by disrupting bacterial membranes. These peptides, particularly D-LL37, offer a promising new strategy for combating drug-resistant TB strains.

Area of Science:

  • Microbiology
  • Drug Discovery
  • Biochemistry

Background:

  • Tuberculosis (TB) remains a global health threat, exacerbated by drug-resistant Mycobacterium tuberculosis (Mtb).
  • Antimicrobial peptides (AMPs) are promising therapeutic agents due to their membrane-targeting mechanism.
  • LL-37, a human cathelicidin, serves as a basis for developing novel anti-TB agents.

Purpose of the Study:

  • To evaluate the antimycobacterial activity and mechanism of action of two rationally designed LL-37-derived peptides.
  • To compare the potency of a truncated analog (LL37-1) and a modified variant (D-LL37) against Mtb.
  • To investigate the effects of these peptides on Mtb membrane integrity and cellular responses.

Main Methods:

  • Dose-response assays to determine inhibitory concentrations (IC90, IC50).
  • Fluorescence-based permeability assays to assess membrane disruption.
  • Scanning electron microscopy (SEM) for ultrastructural analysis of Mtb.
  • RT-qPCR to analyze gene expression changes.

Main Results:

  • D-LL37 demonstrated superior antimycobacterial potency compared to LL37-1.
  • Both peptides induced partial membrane disruption and significant ultrastructural alterations in Mtb.
  • D-LL37 exposure led to the upregulation of P-type ATPase genes (ctpF, ctpA, ctpH).

Conclusions:

  • Optimized LL-37-derived peptides, especially D-LL37, exhibit significant antitubercular activity.
  • The mechanism involves bacterial envelope perturbation and activation of ion transport-related stress responses.
  • These findings highlight the potential of modified LL-37 peptides as novel therapeutics against TB.
Keywords:
LL37 analog peptidesMycobacterium tuberculosisP-type ATPasesantimicrobial peptides

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