A Phase 2 Proof-of-concept Study to Evaluate the Efficacy and Safety of MEDI3902 in Mechanically Ventilated Patients for the Prevention of Nosocomial Pneumonia Caused by Pseudomonas Aeruginosa

Clinical trial looking to evaluate the efficacy and safety of MEDI3902 in mechanically ventilated participants for the prevention of nosocomial pneumonia caused by Pseudomonas aeruginosa.

Start Date25 Mar 2016

Sponsor / Collaborator

MedImmune LLC

[+2]

NCT02255760 / CompletedPhase 1

A Phase 1 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Pharmacokinetics of MEDI3902 in Healthy Adults

This is a Phase 1, randomized, double-blind, placebo-controlled, dose escalation study evaluating the safety and tolerability of a single ascending IV dose of MEDI3902 in healthy adult subjects 18 to 60 years of age.

Start Date04 Sep 2014

Sponsor / Collaborator

MedImmune LLC

100 Clinical Results associated with PslG

100 Translational Medicine associated with PslG

0 Patents (Medical) associated with PslG

Literatures (Medical) associated with PslG

18 Oct 2024·ACS infectious diseases

Virtual Screening Uncovers DspS Activators That Disperse Pseudomonas aeruginosa Biofilms.

Article

Author: Hwang, Siaw San ; Rahman, Taufiq ; Koh, Christabel Ming Ming ; Chee Wezen, Xavier ; Lau, Bee Theng ; Palombo, Enzo A ; Ginjom, Irine Runnie Henry ; Ha, Christopher Heng Xuan

Pseudomonas aeruginosa is the predominant bacterium found in many chronic biofilm infections. Over the past few decades, biofilm-related infections have posed a significant challenge to medical practice due to the increasing emergence of multidrug resistance. Cis-2-decenoic acid (CDA), a small molecule found in P. aeruginosa, has been shown to disperse biofilms formed by various bacteria and to work in synergy with common antibiotics. Despite that, the binding mechanism between CDA and the predicted cyclases/histidine kinases associated sensory extracellular (CHASE) domain of sensor protein DspS remains unknown in the absence of a crystallized protein structure. Moreover, the therapeutic potential of CDA is limited by its susceptibility to oxidative degradation and isomerization. In this work, we propose a structural model for the DspS CHASE domain. The resulting model displays an overall topology reminiscent of the sensor protein PcrK in Xanthomonas campestris. Through molecular dynamics simulations, a stable potential binding site for CDA was further identified. Virtual screening against the predicted site of DspS CHASE using our developed pipeline discovered two promising compounds, compounds 2 and 9, capable of dislodging 7-day P. aeruginosa biofilms at 50 μM without affecting bacterial growth. These compounds also enhanced the effects of ciprofloxacin against P. aeruginosa, reduced the survival of dispersed cells, and increased the expression of matrix-degrading enzyme genes pelA, pslG, and eddA. This study provides insights into CDA recognition by DspS and represents the first large-scale effort to uncover first-in-class DspS activators. At the same time, this work also underscores the effectiveness of a computational-aided drug discovery process in finding new activators, even without a known protein structure.

19 Dec 2023·mBio

cis -DA-dependent dispersion by Pseudomonas aeruginosa biofilm and identification of cis -DA-sensory protein DspS

Article

Author: Amari, Diana ; Davies, David G ; Sauer, Karin ; Kalia, Manmohit

ABSTRACT Native dispersion, the terminal stage in biofilm development, is characterized by the active escape of cells from a biofilm, leaving behind central voids or hollow structures. However, much of what is known about the dispersion mechanism stems from results obtained in experiments using exogenously added dispersion cues such as nitric oxide (NO) and glutamate. To begin exploring the mechanism of native (endogenous) dispersion by Pseudomonas aeruginosa PAO1 biofilms, we examined the similarities between dispersion exogenously induced with NO and the previously reported native dispersion inducer, cis -2-decenoic acid ( cis -DA), as well as native dispersion. Induction of dispersion with cis -DA was similar to induction with NO, with a significant reduction in cyclic dimeric guanosine monophosphate levels compared with uninduced cells but increased expression of pelA , pslG , endA , and eddA . Of those factors known to contribute to P. aeruginosa biofilm dispersion induced by glutamate and NO, only BdlA , AmrZ, RbdA, and DipA were shown to contribute to dispersion induced with cis -DA. The above factors were also shown to contribute to dispersion when no exogenous inducer was added, as indicated by microcolony void formation, a hallmark of native (endogenous) biofilm dispersion. Interestingly, phosphodiesterase PA2133, the previously reported dispersion sensors (NbdA, MucR, and NicD), and a predicted cis -DA sensor PA4892 played no detectable role in native or cis -DA-dependent dispersion. Instead, we show that cis -DA signal sensing by P. aeruginosa required the sensor/response regulator hybrid DspS (PA4112), with inactivation of dspS impairing cis -DA-induced and native dispersion in two P. aeruginosa strains, PAO1 and PA14. Overall, our findings indicate that while sensing of cis -DA and dispersion cues such as NO and glutamate are distinct, the downstream mechanisms leading to the liberation of biofilm cells and, thus, dispersion rely on a shared pathway. IMPORTANCEDispersion is an essential stage of the biofilm life cycle resulting in the release of bacteria from a biofilm into the surrounding environment. Dispersion contributes to bacterial survival by relieving overcrowding within a biofilm and allowing dissemination of cells into new habitats for colonization. Thus, dispersion can contribute to biofilm survival as well as disease progression and transmission. Cells dispersed from a biofilm rapidly lose their recalcitrant antimicrobial-tolerant biofilm phenotype and transition to a state that is susceptible to antibiotics. However, much of what is known about this biofilm developmental stage has been inferred from exogenously induced dispersion. Our findings provide the first evidence that native dispersion is coincident with reduced cyclic dimeric guanosine monophosphate levels, while also relying on at least some of the same factors that are central to the environmentally induced dispersion response, namely, BdlA, DipA, RbdA, and AmrZ. Additionally, we demonstrate for the first time that cis-DA signaling to induce dispersion is attributed to the two-component sensor/response regulator DspS, a homolog of the DSF sensor RpfC. Our findings also provide a path toward manipulating the native dispersion response as a novel and highly promising therapeutic intervention.

01 Dec 2023·Biofilm

Glycosyl hydrolase from Pseudomonas fluorescens inhibits the biofilm formation of Pseudomonads

Article

Author: Yu, Haiying ; Zhang, Zhenyu ; Lei, Fanglin ; Ma, Luyan Z ; Wang, Di ; Naqvi, Syed Tatheer Alam

Biofilms are complex microbial communities embedded in extracellular matrix. Pathogens within the biofilm become more resistant to the antibiotics than planktonic counterparts. Novel strategies are required to encounter biofilms. Exopolysaccharides are one of the major components of biofilm matrix and play a vital role in biofilm architecture. In previous studies, a glycosyl hydrolase, PslG_PA, from Pseudomonas aeruginosa was found to be able to inhibit biofilm formation by disintegrating exopolysaccharide in biofilms. Here, we investigate the potential spectrum of PslG homologous protein with anti-biofilm activity. One glycosyl hydrolase from Pseudomonas fluorescens, PslG_PF, exhibits anti-biofilm activities and the key catalytic residues of PslG_PF are conserved with those of PslG_PA. PslG_PF at concentrations as low as 50 nM efficiently inhibits the biofilm formation of P. aeruginosa and disassemble its preformed biofilm. Furthermore, PslG_PF exhibits anti-biofilm activity on a series of Pseudomonads, including P. fluorescens, Pseudomonas stutzeri and Pseudomonas syringae pv. phaseolicola. PslG_PF stays active under various temperatures. Our findings suggest that P. fluorescens glycosyl hydrolase PslG_PF has potential to be a broad spectrum inhibitor on biofilm formation of a wide range of Pseudomonads.

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