AUTHOR=Mishra Biswajit , Khader Rajamohammed , Felix Lewis Oscar , Frate Marissa , Mylonakis Eleftherios , Meschwitz Susan , Fuchs Beth Burgwyn 

TITLE=A Substituted Diphenyl Amide Based Novel Scaffold Inhibits Staphylococcus aureus Virulence in a Galleria mellonella Infection Model

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.723133

DOI=10.3389/fmicb.2021.723133

ISSN=1664-302X

ABSTRACT=<p>Antimicrobial compounds can combat microbes through modulating host immune defense, inhibiting bacteria survival and growth, or through impeding or inhibiting virulence factors. In the present study, a panel of substituted diphenyl amide compounds previously found to disrupt bacterial quorum sensing were investigated and several were found to promote survival in the <italic>Galleria mellonella</italic> model when provided therapeutically to treat a Gram-positive bacterial infection from methicillin-resistant <italic>Staphylococcus aureus</italic> strain MW2. Out of 21 tested compounds, <italic>N</italic>-4-Methoxyphenyl-3-(4-methoxyphenyl)-propanamide (AMI 82B) was the most potent at disrupting <italic>S</italic>. <italic>aureus</italic> virulence and promoted 50% larvae survival at 120 and 96 h when delivered at 0.5 and 5 mg/Kg, respectively, compared to untreated controls (<italic>p</italic> &lt; 0.0001). AMI 82B did not exhibit <italic>G</italic>. <italic>mellonella</italic> toxicity (<italic>LC</italic><sub>50</sub> &gt; 144 h) at a delivery concentration up to 5 mg/Kg. Further assessment with mammalian cells suggest AMI 82B hemolytic effects against erythrocytes has an <italic>HL</italic><sub>50</sub> greater than the highest tested concentration of 64 μg/mL. Against HepG2 hepatic cells, AMI 82B demonstrated an <italic>LD</italic><sub>50</sub> greater than 64 μg/mL. AMI 82B lacked direct bacteria inhibition with a minimal inhibitory concentration that exceeds 64 μg/mL and no significant reduction in <italic>S</italic>. <italic>aureus</italic> growth curve at the same concentration. Assessment via qPCR revealed that AMI 82B significantly depressed quorum sensing genes <italic>agr</italic>, <italic>spa</italic>, and <italic>icaA</italic> (<italic>p</italic> &lt; 0.05). Thus, AMI 82B therapeutic effect against <italic>S</italic>. <italic>aureus</italic> in the <italic>G</italic>. <italic>mellonella</italic> infection model is likely an influence on bacterial quorum sensing driven virulence factors and provides an interesting hit compound for this medically important pathogen.</p>