Antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance

Area of Science:

• Microbiology
• Molecular Biology
• Drug Discovery

Background:

• New antibiotic candidates are crucial for combating Gram-positive bacterial infections.
• The long-term effectiveness of novel antibiotics is often uncertain due to potential resistance development.

Purpose of the Study:

• To investigate the laboratory evolution of antibiotic resistance in Staphylococcus aureus against preclinical antibiotic candidates.
• To assess cross-resistance patterns between novel candidates and existing antibiotics.
• To understand the molecular mechanisms driving resistance evolution.

Main Methods:

• Laboratory evolution experiments were conducted using Staphylococcus aureus and various antibiotic candidates.
• Cross-resistance was tested against established antibiotics like vancomycin and daptomycin.
• Molecular mechanisms were analyzed through mutation identification in regulatory systems.
• Virulence of resistant strains was evaluated using an invertebrate infection model.

Main Results:

• Antibiotic resistance evolved readily in Staphylococcus aureus for most candidates, except SCH79797.
• Significant cross-resistance was observed between candidates and current clinical antibiotics, including vancomycin, daptomycin, and teixobactin.
• Mutations in regulatory systems were identified as a key driver of resistance and cross-resistance.
• Teixobactin-resistant strains exhibited multidrug resistance and maintained virulence.
• Putative resistance mutations were found to be present in natural bacterial populations.

Conclusions:

• Antibiotic resistance can readily emerge and spread through selection of pre-existing genetic variants.
• Cross-resistance poses a significant threat to the clinical utility of both new and existing antibiotics.
• Early prediction of resistance evolution is critical for successful antibiotic development.