Structure–Activity Relationships of Daptomycin Lipopeptides

Abstract

Daptomycin is a calcium-dependent cyclic lipodepsipeptide derived from the soil saprotroph Streptomyces roseosporus, and its antibiotic properties make it a key agent for treatment of drug-resistant Gram-positive infections. It is most commonly used clinically for the treatment of Gram-positive skin and skin structure infections (SSSI), Staphylococcus aureus bacteremia, and right-sided endocarditis infections associated with S. aureus, including methicillin resistant S. aureus (MRSA). It has also been used "off-label" for Enterococcal infections. There has been a tremendous amount of research investigating its mode of action, resistance mechanisms, and biosynthesis of this clinically important antimicrobial agent. Although we cover the latter aspects in detail, the primary focus of this review is to provide the most comprehensive and up-to-date reference for the medicinal chemist on the structure−activity−toxicity of this important class of lipopeptide antibiotics.

Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane

“…To investigate whether this slight increase in membrane positivity was likely to be sufficient to repel colistin from the membrane, we determined the susceptibility of spheroplasts from E. coli MC1000 mcr-1 or pEmpty to colistin and compared it with the cationic antimicrobial peptides (CAMPs) daptomycin or nisin. Both CAMPs are well characterised for their ability to permeabilize phospholipid bilayers and, like colistin, they are positively charged, enabling us to detect whether the change to membrane charge conferred by MCR-1-modified LPS in the CM contributed specifically to polymyxin resistance [41,42]. Importantly, increased membrane positive charge is a common mechanism of resistance to daptomycin [41].…”

“…Both CAMPs are well characterised for their ability to permeabilize phospholipid bilayers and, like colistin, they are positively charged, enabling us to detect whether the change to membrane charge conferred by MCR-1-modified LPS in the CM contributed specifically to polymyxin resistance [41,42]. Importantly, increased membrane positive charge is a common mechanism of resistance to daptomycin [41].…”

The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions

“…Examples include polymyxins or lipodepsipeptide daptomycin, whose 'tail' aa and lipophilic groups were altered, or depsipeptides ramoplanin and telomycin, whose acylation patterns were modified. [356][357][358][359][360]…”

Organometallic AlaM reagents for umpolung peptide diversification

“…28 In the same category, tryptothionine cross-linked toxic peptides such as actin-binding phalloidin 4 29,30 and RNA polymerase II inhibitor α-amanitin 31,32 from the Amanita phalloides mushroom constitute another class of thioether modifications. Furthermore, variations at the aryl groups resulting from oxidative dimerization of tryptophan such as arylomycins (5) or oxidative cleavage of the indole ring in tryptophan (L-kynurenine in lipopeptide daptomycin 6) 33 give rise to agents with promising antibacterial activities. The unique structural modifications contribute to the diversity of peptides but also represent a synthetic challenge.…”