Abstract
There is a significant need to combat the growing challenge of antibacterial drug resistance. We have previously developed a whole-animal dual-screening platform that first used the nematode Caenorhabditis elegans, to identify low-toxicity antibacterial hits in a high-throughput format. The hits were then evaluated in the wax moth caterpillar Galleria mellonella infection model to confirm efficacy and low toxicity at a whole animal level. This multi-host approach is a powerful tool for revealing compounds that show antibacterial effects and relatively low toxicity at the whole organism level. This paper reports the use of the multi-host approach to identify and validate five new anti-staphylococcal compounds: (1) 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol(PPT), (2) (1S,2S)-2-[2-[[3-(1H-benzimidazol-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-(1-methylethyl)-2-naphthalenyl cyclopropanecarboxylate dihydrochloride(NNC), (3) 4,5,6,7-tetrabromobenzotriazole (TBB), (4) 3-[2-[2-chloro-4-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl] benzoic acid(GW4064), and (5) N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-[(4-iodo-2-methylphenyl)amino] benzamide(PD198306). The compounds reduced the severity of methicillin-resistant Staphylococcus aureus (MRSA, strain MW2) infections in both C. elegans and G. mellonella and showed minimal inhibitory concentrations (MICs) in the range of 2–8 µg/mL. Compounds NNC, PPT, and TBB permeabilized MRSA-MW2 cells to SYTOX green, suggesting that they target bacterial membranes. Compound TBB showed synergistic activity with doxycycline and oxacillin against MRSA-MW2, and compounds PPT, NNC, GW4064, and PD198306 synergized with doxycycline, polymyxin-B, gentamicin, and erythromycin, respectively. The study demonstrates the utility of the multi-host approach with follow-up hit characterization for prioritizing anti-MRSA compounds for further evaluation.
Highlights
StaphylococcusStaphylococcus aureus aureus isolates isolates that that show show resistance resistance to to methicillin methicillin (methicillin-resistantwerefirst firstreported reported in the United Kingdom in and1961,soon andafter, soonin after, in other EuropeanMRSA) were in the Kingdom in 1961, other European countries, countries, Japan,andAustralia, andAccording the US [1].According to Disease the Centers for and Disease Control and
The aim ofeven thisrestore studyclinical was toefficacy characterize the antibacterial properties of five compounds with wereactivity tested against in the presence of five clinical antibiotics fromoriginally different compounds againstMRSA-MW2
Synergic effects, were confirmedand at the whole-animal using in the(Table
Summary
Introduction StaphylococcusStaphylococcus aureus aureus isolates isolates that that show show resistance resistance to to methicillin methicillin (methicillin-resistant (methicillin-resistant S.S. aureus, aureus, MRSA)werefirst firstreported reported in the United Kingdom in and1961,soon andafter, soonin after, in other EuropeanMRSA) were in the Kingdom in 1961, other European countries, countries, Japan,andAustralia, andAccording the US [1].According to Disease the Centers for and Disease Control and. Staphylococcus aureus aureus isolates isolates that that show show resistance resistance to to methicillin methicillin 1961,soon andafter, soonin after, in other European. MRSA) were in the Kingdom in 1961, other European countries, countries, Japan,and. Australia, andAccording the US [1]. According to Disease the Centers for and Disease Control and
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