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

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.