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SEMINAR: Bayliss Seminar Series

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Today's date is Friday, June 05, 2020
Bayliss Seminar Series : Grishma Vadlamani - Understanding the structure and function of proteins involved in inducible AmpC β-lactamase resistance Other events...
The inducible expression of AmpC β-lactamase is a major cause of β-lactam antibiotic resistance in several clinically relevant Gram-negative bacteria, including the opportunistic pathogen Pseudomonas aeruginosa. AmpC induction is regulated by the transcriptional regulator AmpR, which binds to the divergent ampR-ampC operon and is activated by 1,6-anhydromuramoylpeptide an anabolite of peptidoglycan (PG) recycling that is generated by the N-acetyl-β-glucosaminidase NagZ. I will be sharing my findings into the molecular basis of ampC induction based on the structural and biophysical characterization of the archetypal AmpR protein from Citrobacter freundii (CfAmpR). CfAmpR forms a homotetramer that is stabilized by binding the intergenic region of the ampR-ampC operon, and it interacts with up to four repressor ligands (UDP-MurNAc-pentapeptide) in an apparent stepwise manner. Since NagZ generates the AmpR activator ligand, blocking its activity enhances β-lactam efficacy against bacteria with inducible AmpC systems. Crystal structures of NagZ from Burkholderia cenocepacia were determined in complex with the glycosidase inhibitor O-(2-acetamido-2- deoxy-D-glucopyranosylidene)-amino-N-phenylcarbamate (PUGNAc) and its NagZ-selective derivative ethylbutyryl-PUGNAc, 3-acetamido-4,5,6-trihydroxyazepane (MM-124) and its NagZ-selective derivative MM-156, showing that plasticity within the NagZ active site could be exploited to improve the design of inhibitors that selectively bind NagZ over functionally related human N-acetyl-β-glucosaminidases. Furthering an understanding of the role of NagZ inhibition on β-lactam resistance in P. aeruginosa, it was found that the NagZ inhibitor PUGNAc could prevent the emergence of high-level AmpC-mediated β-lactam resistance, and significantly enhanced β-lactam susceptibility in synergy with the potent β-lactamase inhibitor avibactam in an ampC derepressed P. aeruginosa strain. Collectively, this talk offers key insights into the regulatory mechanism of AmpC β-lactamase expression and explores small molecule based strategies to potentiate β-lactam efficacy against Gram-negative bacterial pathogens.
Speaker(s) Grishma Vadlamani - Mylne Lab
Location Bayliss Building Lecture Theatre G33
Contact Academic Services, School of Molecular Sciences <admin-sms@uwa.edu.au> : 08 6488 4414
Start Thu, 13 Jun 2019 12:00
End Thu, 13 Jun 2019 13:00
Submitted by Academic Services, School of Molecular Sciences <admin-sms@uwa.edu.au>
Last Updated Tue, 28 May 2019 14:28
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