2-Aminobenzothiazole based adjuvant of polymyxin E against Gram-negative bacteria

Area of Science:

• Microbiology and Infectious Diseases
• Medicinal Chemistry
• Drug Discovery

Background:

• Antibiotic resistance is a critical global health challenge.
• Polymyxin E, a vital antibiotic, has dose-dependent toxicity limiting its use.
• Antibiotic adjuvants are needed to boost efficacy and reduce polymyxin E dosage.

Purpose of the Study:

• To discover and develop a novel adjuvant to enhance polymyxin E activity.
• To overcome solubility limitations of promising adjuvant candidates.
• To investigate the efficacy and mechanism of the developed adjuvant against resistant bacteria.

Main Methods:

• Screening of an in-house compound library identified KJ1071 as a polymyxin E adjuvant candidate.
• Structure-activity relationship studies led to compound A35 with synergistic activity.
• Structural derivatization of A35 resulted in A59, enhancing aqueous solubility and biological efficacy.

Main Results:

• Compound A59 exhibited a 3237-fold increase in aqueous solubility compared to A35 (3.237 mg/mL).
• A59 significantly potentiated polymyxin E efficacy against diverse Gram-negative bacteria, including resistant strains.
• Mechanism studies suggest A59 targets the bacterial membrane, potentially disrupting its integrity.

Conclusions:

• The novel amino acid derivative A59 effectively enhances polymyxin E activity and overcomes solubility issues.
• A59 demonstrates significant potential as an adjuvant for combating polymyxin E-resistant Gram-negative infections.
• This innovative scaffold offers promising insights for developing new antibiotic adjuvant therapies.