Similarities between Exogenously- and Endogenously-Induced Envelope Stress The Effects of a New Antibacterial Molecule, TPI1609-10 英文参考文献.docVIP

SimilaritiesbetweenExogenously-andEndogenously- InducedEnvelopeStress:TheEffectsofaNew AntibacterialMolecule,TPI1609-10 ShmuelYitzhaki1¤a,JasonE.Rostron1,YanXu1¤b,MarcC.Rideout1,R.NathanAuthement1, StevenB.Barlow1,2¤a,AncaM.Segall1* 1DepartmentofBiologyandCenterforMicrobialSciences,SanDiegoStateUniversity,SanDiego,California,UnitedStatesofAmerica,2ElectronMicroscopyFacility,San DiegoStateUniversity,SanDiego,California,UnitedStatesofAmerica Abstract Antibiotics with novel and/or multiple targets are highly desirable in the face of the steady rise of clinical antibiotic resistance. We have screened and identified small molecules, typified by the compound TPI1609-10 (aka SM10), with antibiotic activity against both gram-positive and gram-negative bacteria. SM10 was screened in vitro to bind branched Holliday junction intermediates of homologous recombination and tyrosine recombinase-mediated recombination; thus, the cellular targets of the small molecules were expected to include the RuvABC Holliday junction resolvasome and the XerCDcomplexinvolvedinpropersegregationofreplicatedchromosomestodaughtercells.SM10indeedinducesDNA damage and filamentation in E. coli. However, SM10 also induces envelope stress and causes increased production of intracellular reactive oxygen species. In addition, SM10 has similar effects to endogenously-induced envelope stress via overproducing outer membrane proteins (OmpC and OmpF), which also induces the SOS response, chromosome fragmentation,andproductionofreactiveoxygenspecies.ThesynergybetweenSM10,andcerulenin,afattyacidsynthesis inhibitor, together with the SM10 hypersensitivity of cpx and rpoE mutants, further support that SM10’s mode of action damages membrane damage. The lethality of SM10 treatment and of OmpC overproduction are observed in both aerobically-andanaerobically-growncells,andisaccompaniedbysubstantialDNAdamageevenanaerobically.Thus,only someDNAdamageisduetoreactiveoxygen.Weproposethatmembranedepolarizationandthepotenti