QseC inhibitors as an antivirulence approach for Gram-negative pathogens.
Invasive pathogens interface with the host and its resident microbiota through interkingdom signaling. The bacterial receptor QseC, which is a membrane-bound histidine sensor kinase, responds to the host stress hormones epinephrine and norepinephrine and the bacterial signal AI-3, integrating interkingdom signaling at the biochemical level. Importantly, the QseC signaling cascade is exploited by many bacterial pathogens to promote virulence. Here, we translated this basic science information into development of a potent small molecule inhibitor of QseC, LED209. Extensive structure activity relationship (SAR) studies revealed that LED209 is a potent prodrug that is highly selective for QseC. Its warhead allosterically modifies lysines in QseC, impairing its function and preventing the activation of the virulence program of several Gram-negative pathogens both in vitro and during murine infection. LED209 does not interfere with pathogen growth, possibly leading to a milder evolutionary pressure toward drug resistance. LED209 has desirable pharmacokinetics and does not present toxicity in vitro and in rodents. This is a unique antivirulence approach, with a proven broad-spectrum activity against multiple Gram-negative pathogens that cause mammalian infections.


OBJECTIVE
There is an imminent need for development of novel treatments for infectious diseases, given that one of the biggest challenges to medicine in the foreseeable future is the emergence of microbial antibiotic resistance. Here, we devised a broad-spectrum antivirulence approach targeting a conserved histidine kinase, QseC, in several Gram-negative pathogens that promotes their virulence expression. The LED209 QseC inhibitor has a unique mode of action by acting as a prodrug scaffold to deliver a warhead that allosterically modifies QseC, impeding virulence in several Gram-negative pathogens.
Meredith M
MM
Curtis
Regan
R
Russell
Cristiano G
CG
Moreira
Adeniyi M
AM
Adebesin
Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
Changguang
C
Wang
Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA.
Noelle S
NS
Williams
Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas, USA.
Ron
R
Taussig
Omm Scientific, Dallas, Texas, USA.
Don
D
Stewart
Department of Urology, UT Southwestern Medical Center, Dallas, Texas, USA.
Philippe
P
Zimmern
Biao
B
Lu
Ravi N
RN
Prasad
Chen
C
Zhu
Department of Microbiology and Immunology and the Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
David A
DA
Rasko
College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, USA.
Jason F
JF
Huntley
John R
JR
Falck
vanessa.sperandio@utsouthwestern.edu.
Vanessa
V
Sperandio
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000502:physiology*; D000071677:Histidine Kinase; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D053038:Quorum Sensing / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014774:Virulence / Q000187:drug effects
D000900:Anti-Bacterial Agents; C531088:LED209; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D011494:Protein Kinases; D000071677:Histidine Kinase