Novel Antibiotics from Marine Invertebrate Microbes

ABSTRACTThe rise of multi drug resistant pathogensparticularly ESKAPE pathogensis a major public health concernOne effective countermeasure against such pathogens is novel antibioticsbut the rate of antibiotic discovery has been in steady declineOne particularly promising source of novel antibiotics is microbial species because most of them have never been cultivated or exploredThis is especially true about marine speciesspecifically microbes living in association with invertebratessuch symbioses are known producers of bioactive compoundsthese compounds likely originate from associated microbesbut only few of them are available in cultureWe have designed and developed several proprietary technology platforms to grow and isolate suchuncultivablemicroorganismsThese platforms are based on a simple ideastrains that do not grow in the lab can be grown in their natural environments if placed into small diffusion chambersCells inside such chambersif returned back to the original environmentwill be naturally fed by nutrients and growth factors diffusing through semipermeable membranesThis approach has resulted in the discovery of several new compoundsincluding teixobactinan exciting new class of antibiotic that is active against resistant pathogensThis general approach can be used to grow invertebrate associatedpreviously uncultivated microorganisms as wellFor this projectwe designed diffusion chambers that are flexible and can assume the topography of the animalthus providing an immediate contact with the hostand the compounds it producesIn preliminary studieswe validated this general approach by growing a diverse collection of novel microorganisms showing antimicrobial activitiesHere we will capitalize on these advances and achieve the following Specific AimsAimDeveloping a method to grow and isolate novel microbial species living in association with marine invertebratesWe will use our new method to isolatemicroorganisms frominvertebrate speciesAimScreening for antimicrobial activityWe will ferment the strains from Aimand screen them against a panel of Gram negative and Gram positive pathogensprioritizingstrains for chemical dereplicationAimChemical dereplication of antimicrobial compoundsUsing traditional separation methodologiesbioassay guided fractionationand high resolution mass spectrometrywe will identify extracts with novel antimicrobial compounds and isolate these compounds into pure substancesWe aim at discoveringnovel compounds with low toxicity and a good spectrum of activity and potencyThe end products of this projectan innovative cultivation platforma large collection of novel marine microorganismsand a selection of antimicrobials they producewill set the stage for development of novel antibiotics in the future Phase II application