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Synergy of outer membrane disruptor SLAP-S25 with hydrophobic antibiotics against Gram-negative pathogens

Zhiqiang Yang1, Meirong Song1, Xiaoyu Li1

  • 1Department of Basic Veterinary Medicine, Key Laboratory of Traditional Chinese Veterinary Medicine Biology, Ministry of Agriculture and Rural Affairs, College of VeterinaryMedicine, China Agricultural University, Beijing 100193, China.

The Journal of Antimicrobial Chemotherapy
|November 17, 2022
PubMed
Abstract

Insights

Combining SLAP-S25 with hydrophobic antibiotics offers a new strategy against multidrug-resistant (MDR) Gram-negative pathogens. This approach enhances antibiotic entry, proving effective in preclinical models.

Area of Science:

  • Microbiology
  • Pharmacology
  • Drug Discovery

Background:

  • Multidrug-resistant (MDR) Gram-negative pathogens pose a significant global health threat.
  • Developing novel therapeutic strategies is crucial to combat these resistant infections.
  • Outer membrane disruption is a potential approach to enhance antibiotic efficacy.

Purpose of the Study:

  • To investigate the synergistic activity of SLAP-S25, an outer membrane disruptor, with hydrophobic antibiotics against MDR Gram-negative pathogens.
  • To evaluate the therapeutic potential of this combination in preclinical models.

Main Methods:

  • Tested the synergistic activity of SLAP-S25 with hydrophobic antibiotics (novobiocin, erythromycin, clindamycin, rifampicin) against five Gram-negative bacteria.
  • Investigated the synergistic mechanism using carbapenem-resistant hypervirulent Klebsiella pneumoniae (CRHvKP4).
  • Assessed in vivo therapeutic activity in a mouse peritonitis/sepsis model.

Main Results:

  • SLAP-S25 disrupts the outer membrane of Gram-negative bacteria by removing lipopolysaccharide (LPS), facilitating antibiotic entry.
  • The combination of SLAP-S25 and rifampicin demonstrated significant therapeutic effects in a mouse model of K. pneumoniae infection.
  • Synergistic activity was observed against tested MDR Gram-negative pathogens.

Conclusions:

  • The combination of SLAP-S25 and hydrophobic antibiotics presents a promising therapeutic strategy against MDR Gram-negative pathogens.
  • SLAP-S25 enhances the efficacy of hydrophobic antibiotics by improving their cellular penetration.
  • This approach could accelerate antibiotic development and reduce treatment costs.

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