Small molecule inhibitors of LcrF, a Yersinia pseudotuberculosis transcription factor, attenuate virulence and limit infection in a murine pneumonia model.
LcrF (VirF), a transcription factor in the multiple adaptational response (MAR) family, regulates expression of the Yersinia type III secretion system (T3SS). Yersinia pseudotuberculosis lcrF-null mutants showed attenuated virulence in tissue culture and animal models of infection. Targeting of LcrF offers a novel, antivirulence strategy for preventing Yersinia infection. A small molecule library was screened for inhibition of LcrF-DNA binding in an in vitro assay. All of the compounds lacked intrinsic antibacterial activity and did not demonstrate toxicity against mammalian cells. A subset of these compounds inhibited T3SS-dependent cytotoxicity of Y. pseudotuberculosis toward macrophages in vitro. In a murine model of Y. pseudotuberculosis pneumonia, two compounds significantly reduced the bacterial burden in the lungs and afforded a dramatic survival advantage. The MAR family of transcription factors is well conserved, with members playing central roles in pathogenesis across bacterial genera; thus, the inhibitors could have broad applicability.
Garrity-Ryan
Lynne K
LK
Paratek Pharmaceuticals, Inc., Boston, MA 02111, USA. lgarrity-ryan@paratekpharm.com
Kim
Oak K
OK
Balada-Llasat
Joan-Miquel
JM
Bartlett
Victoria J
VJ
Verma
Atul K
AK
Fisher
Michael L
ML
Castillo
Cynthia
C
Songsungthong
Warangkhana
W
Tanaka
S Ken
SK
Levy
Stuart B
SB
Mecsas
Joan
J
Alekshun
Michael N
MN
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001562:Benzimidazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality / Q000473:pathology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D014774:Virulence; D015011:Yersinia pseudotuberculosis / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity*; D015012:Yersinia pseudotuberculosis Infections / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality / Q000473:pathology*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D014157:Transcription Factors; C031000:benzimidazole
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