Identification of Micrococcin P2-Derivatives as Antibiotic Candidates against Two Gram-Positive Pathogens

Area of Science:

• Microbiology
• Medicinal Chemistry
• Pharmacology

Background:

• Thiopeptides are potent antimicrobials targeting bacterial protein synthesis, with micrococcins being a less-explored subclass.
• Current treatments for impetigo and Clostridioides difficile infection (CDI) have limitations, necessitating the development of novel therapeutic agents.

Purpose of the Study:

• To computationally simulate micrococcin P2 (MP2) docking and investigate structure-activity relationships (SAR) of micrococcin analogues.
• To identify novel micrococcin analogues with enhanced antimicrobial activity against Gram-positive pathogens, specifically for impetigo and CDI.

Main Methods:

• Computational simulation of micrococcin P2 (MP2) docking.
• Structure-activity relationship (SAR) studies involving the incorporation of nitrogen heterocycles into the micrococcin scaffold.
• In vitro and in vivo testing of synthesized micrococcin analogues (6c and 6d) against impetigo and CDI models.

Main Results:

• Incorporation of specific nitrogen heterocycles significantly enhanced antimicrobial activity.
• Micrococcin analogues 6c and 6d demonstrated superior efficacy against impetigo and CDI, respectively, compared to first-line treatments.
• Compound 6c required a shorter treatment duration for impetigo and downregulated pro-inflammatory cytokines.
• Compound 6d showed no recurrence of CDI and minimal impact on the gut microbiome.

Conclusions:

• Novel micrococcin analogues, 6c and 6d, exhibit potent antimicrobial activity and favorable pharmacokinetic and toxicity profiles.
• These compounds represent promising preclinical candidates for the treatment of impetigo and Clostridioides difficile infection (CDI).
• Further preclinical development is warranted to explore their therapeutic potential.