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

Abstract

Thiopeptides exhibit potent antimicrobial activity against Gram-positive pathogens by inhibiting bacterial protein synthesis. Micrococcins are among the structurally simpler thiopeptides, but they have not been exploited in detail. This research involved a computational simulation of micrococcin P2 (MP2) docking in parallel with the structure-activity relationship (SAR) studied. The incorporation of particular nitrogen heterocycles in the side chain of MP2 enhances the antimicrobial activity. Micrococcin analogues 6c and 6d thus proved to be more effective against impetigo and C. difficile infection (CDI), respectively, as compared to current first-line treatments. Compound 6c also showed a shorter treatment period than that of a first-line treatment for impetigo. This may be attributed to its ability to downregulate pro-inflammatory cytokines. Compound 6d had no observed recurrence for C. difficile and exerted a minimal impact on the beneficial gut microbiome. Their pharmacokinetic properties and low toxicity profile make these compounds ideal candidates for the treatment of impetigo and CDI and validate their involvement in preclinical development.

• Authors: Dahyun Kim, Jusuk Lee, Clovis Shyaka, Jin-Hwan Kwak, Hyunjoo Pai, Mina Rho, Marco A Ciufolini, Minwoo Han, Jong-Hwan Park, Young-Rok Kim, Sungji Jung, Ah-Ra Jang, Eunjung Kim, Jee-Young Lee, Hakyeong Lee, Young-Jin Son, Hee-Jong Hwang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 66 Issue 20 Pg. 14263-14277 (10 26 2023) ISSN: 1520-4804 [Electronic] United States
• PMID: 37796116 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• micrococcin
• micrococcin P2

Topics

• Humans
• Anti-Bacterial Agents (pharmacology, chemistry)
• Impetigo
• Clostridioides difficile