A prospective antibacterial for drug-resistant pathogens: a dual warhead amphiphile designed to track interactions and kill pathogenic bacteria by membrane damage and cellular DNA cleavage

Abstract

A rationally designed bactericidal amphiphile acts on compelling targets and has the potential to disarm resistance development in pathogenic bacteria.

Bioconjugation with Maleimides: A Useful Tool for Chemical Biology

“…Both click probes were sequentially functionalized with Dox‐N 3 and PEG 20000 ‐N 3 yielding an ADC with unaltered binding, internalizing and cytotoxic properties . These advances paved the way to new applications in imaging, theranostics and new dual warhead antibiotics (Scheme A) . More recently DBPD technology has been applied in the production of more complex assemblies of antibody conjugates via controlled loading of two modules (via click handles) on a native antibody scaffold .…”

Potential of Pyridine Amphiphiles as Staphylococcal Nuclease Inhibitor

“…These results have significant implications, as they indicate that C2 can inhibit the activity of the extracellular nuclease of S. aureus even in the complex environment of the spent media; thus, C2 is an interesting prospect for a nuclease inhibitor in therapeutic applications directed against S. aureus . It may also be noted that the minimum inhibitory concentration (MIC) values of C1 and C2 were ascertained by a microtiter broth dilution method and were found to be 200 μg mL −1 (≈0.5 m m ) and 50 μg mL −1 (≈0.1 m m ), respectively. It is quite evident that the MIC values for the amphiphiles are much higher than the concentrations used for studying interactions with the nuclease enzyme.…”

“…The general structure of the pyridine‐based amphiphiles used in the present study is shown in Scheme . The amphiphiles were synthesized through tethering of 1) a pyridine head group (indicated in red in Scheme ), 2) a hydrophobic tail, and 3) a planar fluorogenic pyrene group (indicated in turquoise in Scheme ) for spectroscopic tracking of interactions with DNA and the nuclease enzyme. The amphiphiles differ in the lengths of their hydrophobic tails, with the incorporation of either a 4‐carbon or 12‐carbon chain in C1 or C2, respectively.…”

“…The amphiphiles differed in the lengths of their hydrophobic tails, with the incorporation of either a 4‐carbon or 12‐carbon chain in compound 1 (C1) or compound 2 (C2), respectively. Synthesis and characterization of the amphiphiles was reported in earlier studies …”

Amphiphilic Cargo‐Loaded Nanocarrier Enhances Antibiotic Uptake and Perturbs Efflux: Effective Synergy for Mitigation of Methicillin‐Resistant Staphylococcus aureus

“…In this context, adjuvants that not only act as EPIs, but also demonstrate an inherent membrane‐targeting activity are particularly promising as in addition to efflux inhibition, they are likely to breach the core resistance mechanism in MRSA and enhance the uptake and bactericidal efficacy of a therapeutic antibiotic. Based on this premise, in the present study, we leveraged the membrane‐directed activity of a pyridinium synthetic amphiphile (C1) by developing a C1‐loaded poly(lactic‐co‐glycolic acid) (PLGA) nanocarrier (C1‐PNC), which could potentiate the activity of gentamicin or ciprofloxacin in combinatorial treatment and thereby restore susceptibility of MRSA biofilm to the antibiotics. Mechanistic studies indicated that the adjuvant nanomaterial enhanced gentamicin uptake in MRSA cells, while in case of ciprofloxacin, the nanomaterial hindered efflux of the antibiotic resulting in significant elimination of MRSA cells.…”