Systematic Study of Non‐Natural Short Cationic Lipopeptides as Novel Broad‐Spectrum Antimicrobial Agents

Abstract

We describe the design and synthesis of a new series of non-natural short cationic lipopeptides (MW = 700) as antimicrobial agents. All of the synthesized lipopeptides were tested against a range of microbes such as Gram-positive, Gram-negative bacteria, fungi including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE). By systematic study of design template, we found that three ornithine residues conjugated with myristic acid are minimum requirement for a compound to be an antimicrobial agent. The most potent lipopeptide LP16 possesses broad-spectrum antimicrobial activity and has MICs in the range of 1.5-6.25 μg/mL against Escherichia coli, S. aureus, Pseudomonas aeruginosa, Bacillus subtilis, and MRSE. All lipopeptides showed high selectivity toward microbial strains as compared to human red blood cells (HC50 > 250 μg/mL). Moreover, most potent lipopeptides (LP16 and LP23) did not induce drug resistance in S. aureus even after 15 rounds of passaging. In addition, a representative lipopeptide (LP16) showed tryptic stability for 24 h. These results suggest the potential of short cationic lipopeptides to boost the discovery of future antimicrobial therapeutics.

In Vitro and In Vivo Evaluation of Small Cationic Abiotic Lipopeptides as Novel Antifungal Agents

“…Thus, it seems that the increased hydrophobic bulk of lipopeptides drives them toward zwitterionic membranes, which mimic the membrane of fungi and mammalian cells. These structure–function relationships of lipopeptides support our earlier findings .…”

“…The selective lytic action of most of the lipopeptides against all tested fungal strains motivated us to further assess their in vitro and in vivo potential against clinically relevant fungal strains. In the present report, we have studied the antifungal potential of lipopeptides, selected from our earlier reported library , against drug‐resistant clinical fungal isolates. The membrane perturbation effect of lead lipopeptide was studied using fungal membrane mimicking liposomes.…”

Ultrashort Cationic Lipopeptides–Effect of N-Terminal Amino Acid and Fatty Acid Type on Antimicrobial Activity and Hemolysis

“…Another series of lipopeptides were those with aliphatic (X) side chain that differ in position of the methyl group in peptides with Ile (35)(36)(37)(38), Leu (43)(44)(45)(46) and Nle (63-66) residues. In general, peptides with methyl group that is closer to the backbone of lipopeptide were more hydrophilic.…”

“…For instance, Armas et al noticed that arginine-rich USCLs with a higher net charge (additional arginine residues) suppressed hemolysis; whereas, antimicrobial activity against bacteria was comparable [9]. Moreover, Lohan et al [35] have shown that USCLs with three basic residues had the highest antimicrobial activity among the tested lipopeptides (ornithine; net charge from +1 to +5); but the profile of hemolysis depended mainly on hydrophobicity and therefore on the length of the fatty acid chain. Under experimental conditions histidine imidazole can act as a hydrogen bond acceptor while guanidine moiety of arginine residue as a hydrogen bond donor.…”

Amino acid–based surfactants: New antimicrobial agents

“…Using solid phase synthesis, Lohan et al designed and prepared short lipopeptide molecules consisting of ornithine units conjugated with fatty acids (series 23, Figure 10) [53]. Compounds with ornithine residues ranging from 2 to 5 units and alkyl chain lengths from C12 to C18 showed very good antimicrobial activity against fungi as well as both Gram-positive and Gram-negative bacteria, including clinically relevant methicillin-resistant S. aureus and S. epidermis (MRSA and MRSE), which are resistant to most antibiotics.…”