Target Discovery and Validation

Identification and validation of targets for inhibition by antibiotics is a critical step in antibiotic discovery. Traditional antibiotic discovery programs target cellular constituents that are essential for cell proliferation and survival. More recently, the focus shifted to targets essential under specific conditions, such as acute bacterial infections, biofilms, or targets playing an essential role in development of antibiotic resistance. The Center explores bacterial chromosome maintenance, multidrug efflux and autophagy as potential targets for novel antibiotics.

Chromosome structure

Condensins play a key role in chromosome packing and segregation. In several bacteria, inactivation of condensins leads to dramatic chromosome segregation defects and a reduction in cell viability. In others, condensins are essential for virulence. Importantly, condensins are rate-limiting enzymes in the chromosome maintenance pathway and can be inhibited by small molecules. These features make these proteins a promising new target for antibacterials. Current efforts are directed on validation of condensins as targets for inhibition in animal models of bacterial infections and identification of other plausible targets involved in chromosome metabolism.

Petrushenko, Z.M., et al., Novobiocin Susceptibility of MukBEF-Deficient Escherichia coli Is Combinatorial with Efflux and Resides in DNA Topoisomerases. Antimicrob Agents Chemother, 2016. 60(5): p. 2949-53. DOI: 10.1128/AAC.03102-15
Zhao, H., et al., Pseudomonas aeruginosa Condensins Support Opposite Differentiation States. J Bacteriol, 2016. 198(21): p. 2936-2944. DOI: 10.1128/JB.00448-16

RND Efflux Pumps

The most effective multidrug efflux transporters are from Resistance-Nodulation-Division (RND) superfamily. They associate with the periplasmic and outer membrane accessory proteins to form trans-envelope complexes that confer resistance to all clinically significant antibiotics. Ultimately, these efflux machines enable conversion of the energy stored in the inner membrane into active transport of antibiotics across the outer membrane. Mutational inactivation or inhibition of efflux pumps dramatically potentiate activities of various antibiotics in P. aeruginosa, pointing out the central role of active efflux by multidrug transporters in limiting drug permeation into this and other Gram-negative bacteria. The Center is focused on validation of RND efflux pumps from P. aeruginosa for inhibition by small molecules.

Abdali, N., J.M. Parks, K.M. Haynes, J.L. Chaney, A.T. Green, D. Wolloscheck, J.K. Walker, V.V. Rybenkov, J. Baudry, J.C. Smith, and H.I. Zgurskaya, Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump. ACS Infect Dis, 2017. 3(1): p. 89-98 DOI: 10.1021/acsinfecdis.6b00167