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Characterization of Five Novel Anti-MRSA Compounds Identified

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Characterization of Five Novel Anti-MRSA Compounds Identified antibiotics Article Characterization of Five Novel Anti-MRSA Compounds Identified Using a Whole-Animal Caenorhabditis elegans/Galleria mellonella Sequential-Screening Approach Rajamohammed Khader 1, Nagendran Tharmalingam 1 , Biswajit Mishra 1, LewisOscar Felix 1, Frederick M. Ausubel 2,3 , Michael J. Kelso 4,5 and Eleftherios Mylonakis 1,* 1 Infectious Diseases Division, Department of Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA; [email protected] (R.K.); [email protected] (N.T.); [email protected] (B.M.); [email protected] (L.F.) 2 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; [email protected] 3 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA 4 Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong 2522, Australia; [email protected] 5 Illawarra Health and Medical Research Institute, University of Wollongong, Northfields Avenue, Wollongong 2522, Australia * Correspondence: [email protected]; Tel.: +1-401-444-7856 Received: 28 June 2020; Accepted: 24 July 2020; Published: 27 July 2020 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) 4,40,4”-(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-tetrabromobe nzotriazole (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. Keywords: antibiotic; high-throughput screening (HTS), MRSA; MIC; Caenorhabditis elegans; Galleria mellonella Antibiotics 2020, 9, 449; doi:10.3390/antibiotics9080449 www.mdpi.com/journal/antibiotics Antibiotics 2020, 9, x FOR PEER REVIEW 2 of 12 Keywords: antibiotic; high-throughput screening (HTS), MRSA; MIC; Caenorhabditis elegans; Galleria mellonella Antibiotics 2020, 9, 449 2 of 12 1. Introduction Introduction Staphylococcus aureus aureus isolatesisolates that that show show resistance resistance to to methicillin methicillin (methicillin-resistant (methicillin-resistant S.S. aureus aureus,, MRSA) werewere firstfirst reported reported in thein the United United Kingdom Kingdo inm 1961, in and1961, soon and after, soon in after, other Europeanin other European countries, countries,Japan, Australia, Japan, andAustralia, the US [and1]. According the US [1]. to theAccording Centers forto Diseasethe Centers Control for andDisease Prevention Control (CDC), and Preventionin the US, there (CDC), are in more the thanUS, there 35,000 are deaths more and than 90,000 35,000 severe deaths cases and of 90,000 MRSA severe infection cases each of yearMRSA [2]. infectionVancomycin each is year typically [2]. Vancomycin the antibiotic is of typically choice for the treating antibiotic serious of choice Gram-positive for treating bacterial serious infections, Gram- positiveincluding bacterial MRSA, infections, but reports including of vancomycin-resistant MRSA, but reports and of vancomycin-intermediate vancomycin-resistant andS. aureusvancomycin-strains intermediateare becoming S. more aureus common strains [are3]. becoming more common [3]. Whole animal-based high-throughput high-throughput screening screening (HTS) (HTS) is is a powerful tool for discovering antibacterial compounds, compounds, including including those those that that would otherwise be missed by traditional antibiotic screens that report compounds that inhibit bacteria bacteriall growth [[4].4]. Our Our laboratory laboratory has has developed developed a a fully fully automated HTS platform that utilizes the nematode nematode Caenorhabditis elegans toto identify identify compounds compounds that that cure Staphylococcus aureus (MRSA) [5], [5], Enterococcus faecalis [6],[6], or or PseudomonasPseudomonas aeruginosa [7][7] infections infections inin C. eleganseleganswithout without showing showing frank frank host host toxicity toxicity that that results results in the in deaththe death of the of nematodes. the nematodes. Since Since these thesepathogens pathogens kill C. kill elegans C. elegans, hit compounds, hit compounds are those are thatthose reduce that reduceC. elegans C. eleganskilling, killing, resulting resulting in an excess in an excessof live wormsof live compared worms tocompared non-treated to pathogen-infectednon-treated pathogen-infected nematodes. Highly nema toxictodes. compounds Highly dotoxic not compoundsemerge as hits do innot the emerge assay, as because hits in they the as killsay, the because nematodes. they kill the nematodes. Here, we describe the coupling of the C. elegans HTS platform with a secondary screen that uses MRSA infectioninfection of ofGalleria Galleria mellonella mellonella(wax moth)(wax larvaemoth) (caterpillars)larvae (caterpillars) to validate to the validate anti-staphylococcal the anti- staphylococcalactivity and low activity whole-animal and low toxicity whole-animal of hit compounds toxicity of athit the compounds whole-organism at the whole-organism level [8]. In this study,level [8].we usedIn this the study, dual-host we approachused the todual-host identify approa and validatech to fiveidentify new and anti-MRSA validate compounds, five new anti-MRSA and report compounds,follow-up characterization and report follow-up of their characterization antibacterial and of other their properties. antibacterial and other properties. 2. Results Results 2.1. Identification Identification of of Compounds Compounds That Bloc Blockk the Ability of MRSA to Kill C. elegans We previously reportedreported thatthat highhigh throughput throughput screening screening for for compounds compounds that that reduce reduce the the ability ability of ofMRSA MRSA to to kill killC. C. elegans elegansyielded yielded 185 185 hits hits from from a total a total of 82,000of 82,000 unique unique compounds compounds tested tested [9]. [9]. Among Among the the185 185 hits, hits, five five compounds compounds that prolongedthat prolongedC. elegans C. eleganssurvival survival at a screening at a screening concentration concentration of 2.86 ofµg 2.86/mL µg/mL(PPT, NNC, (PPT, TBB, NNC, GW4064, TBB, GW4064, and PD198306; and PD198306; Figure1 )Figure were chosen1) were for chosen further for evaluation, further evaluation, because: because:(1) previous (1) previous studies hadstudies reported had reported some form some of form bioactivity of bioactivity for each for and each (2) and their (2) Z-scores their Z-scores in the inC. theelegans C. elegansscreen screen were higher were higher than 2.0, than indicating 2.0, indicati a robustng a robust response response (Tables (Tables1 and2). 1 and 2). FigureFigure 1. 1. ChemicalChemical structures structures of of PPT PPT,, NNC, TBB, GW4064, and PD198306. 2 Antibiotics 2020, 9, 449 3 of 12 Table 1. List of compound names and reported bioactivities. Compounds Chemical Name Reported Bioactivity Prevents ovariectomy-induced weight gain and loss of bone mineral PPT 4,40,4”-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol density, and induces gene expression in the hypothalamus following systemic administration in vivo [10]. Highly selective T-type calcium (1S,2S)-2-[2-[[3-(1H-Benzimidazol-2- channel blocker. Displays IC50 yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4- values of 6.8 and >100 µM for NNC tetrahydro-1-(1-methylethyl)-2-naphthalenyl inhibition of Cav3.1 T-type channels cyclopropanecarboxylate dihydrochloride and HVA currents respectively in INS-1 cells [11]. Cell-permeable, selective inhibitor of casein kinase-2.Exhibits modest TBB 4,5,6,7-Tetrabromobenzotriazole discrimination between CK2 subunits [12]. Selective, non-steroidal farnesoid X 3-[2-[2-Chloro-4-[[3-(2,6-dichlorophenyl)-5-(1- receptor (FXR) agonist Shown to GW4064 methylethyl)-4- suppress autophagy in isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid nutrient-deprived mouse hepatocytes
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