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2020-03-10Zeitschriftenartikel DOI: 10.25646/6927
Loss of the Periplasmic Chaperone Skp and Mutations in the Efflux Pump AcrAB-TolC Play a Role in Acquired Resistance to Antimicrobial Peptides in Salmonella typhimurium
dc.contributor.authorKapach, Gal
dc.contributor.authorNuri, Reut
dc.contributor.authorSchmidt, Christiane
dc.contributor.authorDanin, Adi
dc.contributor.authorFerrera, Shir
dc.contributor.authorSavidor, Alon
dc.contributor.authorGerlach, Roman G.
dc.contributor.authorShai, Yechiel
dc.date.accessioned2020-05-28T12:48:39Z
dc.date.available2020-05-28T12:48:39Z
dc.date.issued2020-03-10none
dc.identifier.other10.3389/fmicb.2020.00189
dc.identifier.urihttp://edoc.rki.de/176904/6813
dc.description.abstractBacterial resistance to antibiotics is a major concern worldwide, leading to an extensive search for alternative drugs. Promising candidates are antimicrobial peptides (AMPs), innate immunity molecules, shown to be highly efficient against multidrug resistant bacteria. Therefore, it is essential to study bacterial resistance mechanisms against them. For that purpose, we used experimental evolution, and isolated a Salmonella enterica serovar typhimurium-resistant line to the AMP 4DK5L7. This AMP displayed promising features including widespread activity against Gram-negative bacteria and protection from proteolytic degradation. However, the resistance that evolved in the isolated strain was particularly high. Whole genome sequencing revealed that five spontaneous mutations had evolved. Of these, three are novel in the context of acquired AMP resistance. Two mutations are related to the AcrAB-TolC multidrug efflux pump. One occurred in AcrB, the substrate-binding domain of the system, and the second in RamR, a transcriptional regulator of the system. Together, the mutations increased the minimal inhibitory concentration (MIC) by twofold toward this AMP. Moreover, the mutation in AcrB induced hypersusceptibility toward ampicillin and colistin. The last mutation occurred in Skp, a periplasmic chaperone that participates in the biogenesis of outer membrane proteins (OMPs). This mutation increased the MIC by twofold to 4DK5L7 and by fourfold to another AMP, seg5D. Proteomic analysis revealed that the mutation abolished Skp expression, reduced OMP abundance, and increased DegP levels. DegP, a protease that was reported to have an additional chaperone activity, escorts OMPs through the periplasm along with Skp, but is also associated with AMP resistance. In conclusion, our data demonstrate that both loss of Skp and manipulation of the AcrAB-TolC system are alternative strategies of AMP acquired resistance in Salmonella typhimurium and might represent a common mechanism in other Gram-negative bacteria.eng
dc.language.isoengnone
dc.publisherRobert Koch-Institut
dc.rights(CC BY 3.0 DE) Namensnennung 3.0 Deutschlandger
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/de/
dc.subjectantimicrobial peptide (AMPs)eng
dc.subjectbacterial resistanceeng
dc.subjectAcrAB-TolCeng
dc.subjectramReng
dc.subjectSkpeng
dc.subjectperiplasmeng
dc.subjectefflux pumpeng
dc.subject.ddc610 Medizin und Gesundheitnone
dc.titleLoss of the Periplasmic Chaperone Skp and Mutations in the Efflux Pump AcrAB-TolC Play a Role in Acquired Resistance to Antimicrobial Peptides in Salmonella typhimuriumnone
dc.typearticle
dc.identifier.urnurn:nbn:de:kobv:0257-176904/6813-7
dc.identifier.doihttp://dx.doi.org/10.25646/6927
dc.type.versionpublishedVersionnone
local.edoc.container-titlefrontiers in Microbiologynone
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttps://www.frontiersin.org/articles/10.3389/fmicb.2020.00189/fullnone
local.edoc.container-publisher-namefrontiersnone
local.edoc.container-volume11none
local.edoc.container-issue189none
local.edoc.container-year2020none
local.edoc.container-firstpage1none
local.edoc.container-lastpage17none
local.edoc.rki-departmentProjektgruppen/Nachwuchsgruppennone
dc.description.versionPeer Reviewednone

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