Targeting membrane-bound bacterial cell wall precursors: a tried and true antibiotic strategy in nature and the clinic

Abstract

Since Fleming’s discovery of penicillin nearly a century ago, a bounty of natural product antibiotics have been discovered, many of which continue to be of clinical importance today. The structural...

Real-Time Biosynthetic Reaction Monitoring Informs the Mechanism of Action of Antibiotics

“…This MoA is exemplified by amphomycin, bacitracin, nisin, ramoplanin, and vancomycin. 45 Since the targeted precursors are nonproteinaceous in nature, they are not easily mutated or modified. Consequently, they continue to hold promise for antibiotic discovery and development.…”

“…Most of the antibiotics that interfere with this peptidoglycan biosynthesis pathway appear to specifically act by sequestering the key membrane-bound intermediates, namely, C 55 -P, C 55 -PP, lipid-I, and lipid-II, rather than by targeting the enzymes themselves. This MoA is exemplified by amphomycin, bacitracin, nisin, ramoplanin, and vancomycin . Since the targeted precursors are nonproteinaceous in nature, they are not easily mutated or modified.…”

Discovery and Derivatization of Tridecaptin Antibiotics with Altered Host Specificity and Enhanced Bioactivity

“…Bacillus and Paenibacillus produce a range of other classes of lipopeptides that act on MDR Gram-negative pathogens, including brevicidines, laterocidines, relacidines, paenibacterins, and tridecaptins. − Of these, tridecaptins stand out as they possess a mechanism of action that is distinct from that of the aforementioned lipopeptides. In addition to interacting with lipopolysaccharides (LPS), tridecaptins also bind to Gram-negative lipid II and in doing so cause the disruption of the proton motive force. − This unique dual mechanism of action reduces the likelihood of cross-resistance . Since the discovery of tridecaptin A in 1978, multiple tridecaptin variants with modifications at either the N-terminal fatty acid moiety or in the amino acid sequence have been reported.…”

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

“…It is synthesized on the inner leaflet of the cytoplasmic membrane, before translocation to the outer leaflet, where it is then used as the monomeric building block of peptidoglycan biosynthesis. Lipid II is a validated antibiotic target for clinically prescribed antibiotics including vancomycin and ramoplanin [ 2 ]. It is also the target for a host of other antimicrobials (mostly non-ribosomal peptides), including the tridecaptins [ 3 ], nisin [ 4 ], teixobactin [ 5 ], clovibactin [ 6 ], malacidin [ 7 ], and cilagicin [ 8 ].…”

“…These structural modifications are described in detail by Münch and co-workers [ 9 ]. For more details on lipid II-binding antimicrobials, see recent review by Buijs and co-workers [ 2 ].…”