Abstract
The increasing resistance of bacteria to available antibiotics has stimulated the search for new antimicrobial compounds with less specific mechanisms of action. These include the ability to disrupt the structure of the cell membrane, which in turn leads to its damage. In this context, amphiphilic lipopeptides belong to the class of the compounds which may fulfill this requirement. In this paper, we describe two linear analogues of battacin with modified acyl chains to tune the balance between the hydrophilic and hydrophobic portion of lipopeptides. We demonstrate that both compounds display antimicrobial activity with the lowest values of minimum inhibitory concentrations found for Gram-positive pathogens. Therefore, their mechanism of action was evaluated on a molecular level using model lipid films mimicking the membrane of Gram-positive bacteria. The surface pressure measurements revealed that both lipopeptides show ability to bind and incorporate into the lipid monolayers, resulting in decreased ordering of lipids and membrane fluidization. Atomic force microscopy (AFM) imaging demonstrated that the exposure of the model bilayers to lipopeptides leads to a transition from the ordered gel phase to disordered liquid crystalline phase. This observation was confirmed by attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) results, which revealed that lipopeptide action causes a substantial increase in the average tilt angle of lipid acyl chains with respect to the surface normal to compensate for lipopeptide insertion into the membrane. Moreover, the peptide moieties in both molecules do not adopt any well-defined secondary structure upon binding with the lipid membrane. It was also observed that a small difference in the structure of a lipophilic chain, altering the balance between hydrophobic and hydrophilic portion of the molecules, results in different insertion depth of the active compounds.
Highlights
The resistance of pathogens to available antibiotics is an increasingly serious problem in modern medicine [1]
Considering this divergence in conjunction with the differences in the hydration of the lipid ester group, this may indicate that the plane of amide bonds in LC10-OP was almost parallel to the plane of the bilayer, while, in BC10-OP, the peptide moiety either adopted a slightly more tilted orientation or its molecular axis was rotated, enabling deeper insertion of the lipopeptide into the membrane. Such an interpretation is in line with the results of surface pressure measurements, where more efficient insertion was observed for BC10-OP. We demonstrated that both LC10-OP and BC10-OP display antimicrobial activity with the lowest values of minimum inhibitory concentrations found for Gram-positive S. aureus and S. epidermidis
Due to the amphipathic nature of the lipopeptides, the most probable target of their antimicrobial action is the cell membrane. The mechanism of their action was evaluated on a molecular level using model lipid films composed of DPPG/POPG/CL mimicking the membrane of Gram-positive bacteria
Summary
The resistance of pathogens to available antibiotics is an increasingly serious problem in modern medicine [1]. A possible solution to this problem involves the use of compounds with less specific action, based, for example, on damaging the bacterial cell membrane. This condition is met by antimicrobial peptides targeting the bacterial cell membranes [2,3]. They interact preferentially with negatively charged membranes of bacterial cells, and their amphiphilic structure allows them to insert into the core of the membrane [4] Such a model of action is widely accepted since the bactericidal kinetics of antimicrobial peptides is often correlated with the depolarization of the cell membrane. Examples include daptomycin and polymyxins [7,8]
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