Speaker: Olga Genilloud, Fundacion Medina
Date: Tuesday, March 2nd, 2021, 15.30 p.m
Free Zoom dial in: https://zoom.us/j/92238793287
Meeting ID: 922 3879 3287
Speaker: Klaas Martin Pos
Tuesday, Feb 9, 3.30 p.m
Zoom dial in: https://zoom.us/j/99954059823
Gram-negative bacteria maintain an intrinsic resistance mechanism against entry of noxious compounds by utilizing highly efficient tripartite efflux pumps. The archetype E. coli AcrAB-TolC tripartite drug efflux pump contains the inner membrane H+/drug antiporter AcrB comprising three functionally interdependent protomers, cycling consecutively through the loose (L), tight (T) and open (O) state during cooperative catalysis. The L protomer access pocket (AP) and T protomer deep binding pocket (DBP) inside the periplasmic porter domain (PD) have the propensity to bind many different antimicrobials. On the other hand, the transmembrane domain of AcrB is until now postulated only to be involved in the energy transduction by binding and releasing protons, giving directionality to the postulated „LTO“ conformational cycling.
Klaas Martin Pos will present structural and functional data suggesting that the transmembrane domain is involved in allosteric drug binding.
Date: Tuesday, January, 26th 2021 at 2 pm
Dial in via Zoom: https://zoom.us/j/91220440925
"Gram-negative bacteria have evolved a complex double-membrane cell envelope, with the two membranes having orthogonal sieving properties. A number of potential antibacterial compounds with intracellular targets fail to inhibit gram-negatives because they are prevented from reaching their targets within the cell by this double-membrane barrier. Quantifying and understanding antibiotic transport across these membranes is hence crucial for the rational design of new antibiotics.
We have developed multiple, complementary approaches to study this problem. One set of assays quantifies antibiotic transport across well-defined biomimetic vesicle membranes, where transport across lipid barriers and porins can be precisely measured in a range of conditions. These methods synergise with whole-cell approaches and mathematical modelling that we have developed, where antibiotic accumulation can be studied in individual bacteria trapped in a microfluidic device in real-time. These complementary biophysical approaches offer new tools to investigate this complex membrane transport phenomenon, which will in turn benefit academic and industry scientists developing new antibacterial compounds."
Dial in via Zoom: https://zoom.us/j/98886770244
Abstract: Antibiotics that inhibit multiple bacterial targets offer a promising therapeutic strategy against resistance evolution, but developing such antibiotics is challenging. Here we demonstrate that a rational design of balanced multitargeting antibiotics is feasible by using a medicinal chemistry workflow. The resultant lead compounds belonging to a novel chemical class, almost equipotently inhibit bacterial DNA gyrase and topoisomerase IV complexes and interact with multiple evolutionary conserved amino acids in the ATP-binding pockets of their target proteins. Compounds are excellently potent against a broad range of gram-positive bacteria.