Abstract
Escalating multidrug resistance and highly evolved virulence mechanisms have aggravated the clinical menace of methicillin-resistant Staphylococcus aureus (MRSA) infections. Towards development of economically viable staphylocidal agents here we report eight structurally novel tryptophan-arginine template based peptidomimetics. Out of the designed molecules, three lipopeptidomimetics (S-6, S-7 and S-8) containing 12-amino dodecanoic acid exhibited cell selectivity and good to potent activity against clinically relevant pathogens MRSA, methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant Enterococcus faecium (MIC: 1.4–22.7 μg/mL). Mechanistically, the active peptidomimetics dissipated membrane potential and caused massive permeabilization on MRSA concomitant with loss of viability. Against stationary phase MRSA under nutrient-depleted conditions, active peptidomimetics S-7 and S-8 achieved > 6 log reduction in viability upon 24 h incubation while both S-7 (at 226 μg/mL) and S-8 (at 28 μg/mL) also destroyed 48 h mature MRSA biofilm causing significant decrease in viability (p < 0.05). Encouragingly, most active peptidomimetic S-8 maintained efficacy against MRSA in presence of serum/plasma while exhibiting no increase in MIC over 17 serial passages at sub-MIC concentrations implying resistance development to be less likely. Therefore, we envisage that the current template warrants further optimization towards the development of cell selective peptidomimetics for the treatment of device associated MRSA infections.
Highlights
cationic antimicrobial peptides (CAMPs) are small stretches of amino acid residues (16–50) which represent evolutionarily conserved components of host defense against invading microbes[16]
The utility of enhanced hydrophobicity in promoting efficacy is not restricted to CAMP mimics only as clinical antibiotics like oritavancin, teicoplanin and telavancin are reported to cause enhanced membrane permeability in microbes owing to better anchoring in bacterial cells due to the presence of appended hydrophobic side chains[37,38]
Containing 12-amino dodecanoic acid moiety were found to exhibit good to potent growth inhibitory activities against clinically relevant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant S. epidermidis and Vancomycin-resistant enterococci (VRE)
Summary
CAMPs are small stretches of amino acid residues (16–50) which represent evolutionarily conserved components of host defense against invading microbes[16]. In our efforts to design cost-effective (short), resistance proof and membrane disruptive antibacterial peptides/peptidomimetics, we have explored the effect of increasing cationic charge by rational substitution of amino acids or modulation of hydrophobicity by using various N- and C-terminal unnatural modifications[23,24,25,26]. We sought to develop short (5-mer), membrane disruptive, protease-stable peptidomimetics by incorporating unnatural moieties in the middle of the sequences to better fine tune hydrophobicity and activity/selectivity. Using these designed peptidomimetics we further explored the perspective that compared to conventional antibiotics membrane disruptive agents are better effective against biofilms. We assessed kill kinetics of the active peptidomimetics against stationary phase MRSA in nutrient-depleted medium and extended the work against 48 h mature biofilms to evaluate their efficacy in biofilm model
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