Novel Miniature Membrane Active Lipopeptidomimetics against Planktonic and Biofilm Embedded Methicillin-Resistant Staphylococcus aureus

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.Pan-resistant microbial pathogens refractory to current clinical antibiotics are spreading at an unprecedented rate 1 . Among human pathogens, methicillin-resistant Staphylococcus aureus (MRSA) is a high priority clinical threat 2 . Multidrug resistance and expression of multiple virulence factors have further exacerbated the clinical severity of MRSA infections in clinics as well as community settings 3 . Moreover, with the growing use of medical implants in clinics, almost 65-80% MRSA infections in vivo have been reported to be associated with biofilm formation. Biofilms are large agglomerations of bacterial cells encased in a self-produced matrix that exhibit substantial recalcitrance to antibiotic treatment 4 (10 to 1000-fold more antibiotic concentration is required to eradicate biofilms). The recalcitrance of biofilms is multifactorial involving high localized inoculum, poor penetration of antibiotics to the core of biofilms, slow-growing nutrient-depleted bacterial populations and presence of persister cells 5,6 . Additionally, matrix formation allows the creation of a microenvironment which promotes resistance and tolerance development in microbes along with providing protection from host immune surveillance 7 . Therefore, a lot of efforts are being directed towards optimization of novel molecules/strategies to eradicate clinically relevant biofilms [8][9][10] . Recently, the consensus is emerging that unlike single target capturing antibiotics; membrane disruptive, dual target...

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

“…There are eleven (10, 25, 26, 45, 46, 49, 50, 66, 69, 81, 82) USCLs being less active against MRSA strain and four ones (54, 74, 97, 98) with lower MIC against this strain, while MIC was no more than two-fold different. Similarly, Joshi et al [50] have not reported essential differences in antistaphylococcal activity of cationic lipopeptidomimetics against planktonic cultures of S. aureus ATCC 25923 and ATCC 33591. In that study, no significant differences in antimicrobial activity against E. faecium ATCC 29212 and vancomycin-resistant strain (ATCC 700221) were noticed.…”

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Effects of stigmata maydis on the methicillin resistantStaphylococus aureusbiofilm formation

“…Since Staphylococcus aureus has the ability to form biofilms and is resistant to many antibiotics, it causes chronic bovine mastitis, which is difficult to treat (Cramton et al, 1999). Moreover, methicillin resistance of Staphylococcus aureus could further complicate the treatment of this disease (Joshi et al, 2018; Lowy, 2003).…”