Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity

The problem of antibiotic resistance
has prompted the search for
new antibiotics with novel mechanisms of action. Analogues of the
A54556 cyclic acyldepsipeptides (ADEPs) represent an attractive class
of antimicrobial agents that act through dysregulation of caseinolytic
protease (ClpP). Previous studies have shown that ADEPs are active
against Gram-positive bacteria (e.g., MRSA, VRE, PRSP (penicillin-resistant Streptococcus pneumoniae)); however, there are currently
few studies examining Gram-negative bacteria. In this study, the synthesis
and biological evaluation of 14 novel ADEPs against a variety of pathogenic
Gram-negative and Gram-positive organisms is outlined. Optimization
of the macrocyclic core residues and N-acyl side
chain culminated in the development of 26, which shows
potent activity against the Gram-negative species Neisseria
meningitidis and Neisseria gonorrheae and improved activity against the Gram-positive organisms Staphylococcus aureus and Enterococcus
faecalis in comparison with known analogues. In addition,
the co-crystal structure of an ADEP–ClpP complex derived from N. meningitidis was solved.