A broad-spectrum antibiotic adjuvant reverses multidrug-resistant Gram-negative pathogens

Area of Science:

• Microbiology
• Infectious Diseases
• Drug Discovery

Background:

• Multidrug-resistant (MDR) bacterial pathogens, particularly carbapenem-resistant Enterobacteriaceae (CRE), present a significant global health threat.
• The limited antibiotic development pipeline necessitates innovative strategies, such as antibiotic adjuvants, to combat resistant infections.

Purpose of the Study:

• To investigate the potential of a short linear antibacterial peptide (SLAP)-S25 as an antibiotic adjuvant.
• To evaluate SLAP-S25's ability to enhance the efficacy of existing antibiotics against MDR Gram-negative pathogens.

Main Methods:

• SLAP-S25, containing non-natural amino acids, was synthesized and tested for antibacterial activity.
• The peptide's synergistic effects with various antibiotic classes (cefepime, colistin, ofloxacin, rifampicin, tetracycline, vancomycin) were assessed against MDR Gram-negative bacteria.
• Mechanistic studies explored SLAP-S25's interaction with bacterial membranes (lipopolysaccharide and phosphatidylglycerol).
• In vivo efficacy was evaluated in animal models of multidrug-resistant Escherichia coli infections.

Main Results:

• SLAP-S25 exhibited weak intrinsic antibacterial activity but significantly boosted the efficacy of multiple antibiotic classes against MDR Gram-negative pathogens.
• Mechanistic studies revealed SLAP-S25 induces membrane damage by targeting both outer and cytoplasmic bacterial membranes.
• SLAP-S25 effectively enhanced colistin's activity against MDR E. coli in multiple animal infection models.

Conclusions:

• SLAP-S25 serves as a potent broad-spectrum antibiotic adjuvant, revitalizing existing antibiotics against challenging MDR Gram-negative infections.
• This peptide offers a promising therapeutic strategy, enhancing current antibiotic treatments and addressing the critical need for solutions against global antimicrobial resistance.