Developing therapeutic options directed against
multi-resistant Gram-negative bacteria

Drug resistance presents an ever-increasing threat to public health and encompasses all major microbial pathogens and antimicrobial drugs. The major factor defining the high intrinsic and acquired multidrug resistance of Gram-negative pathogens is their low cell wall permeability.

The Center for Antibiotic Discovery and Resistance discovers fundamental principles that govern permeation of antibiotics into bacterial cells and utilizes them for the development of novel small molecule therapeutics effective against antibiotic resistant Gram-negative bacteria. Research Fellowships are available.

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The Center is working on five projects:

Bacterial Physiology of Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic human pathogen responsible for numerous infections in patients with compromised immune system or pulmonary disease, burn victims or those in ICU. The Center investigates cell biology of P. aeruginosa seeking to understand the mechanisms that underlie its pathogenicity and finding novel ways to control it.
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Target Discovery and Validation

The Center seeks novel targets suitable for small molecule therapeutics, validates them using animal models and develops inhibitors against them. The current thrust areas include chromosome maintenance, multidrug efflux and autophagy. Several targets have been selected for drug discovery and other promising candidates are being characterized.  Learn more

Drug Discovery

We use experimental and in silico screening to find new antibacterials. Three projects are currently under way, including the development of condensin inhibitors, inhibitors of efflux pumps and activators of ClpXP protease.
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Efflux Mechanisms

Multidrug efflux pumps define the intracellular concentrations and hence potencies of antibacterial agents. These multiprotein membrane complexes actively pump antibiotics out from cells. We are working on understanding substrate specificities of efflux pumps and possible mechanisms of their avoidance and inhibition.  Learn more

Drug Permeation

The two-membrane cell envelope of Gram-negative and some Gram-positive pathogens creates a formidable barrier for permeation of most amphiphilic drugs. The center uses recently developed genetic, mathematical and computational tools to identify physico-chemical properties of drugs that enable their permeation into bacterial cells. Learn more

The Center just published the application of our technology to a designed library of oxazolidinones: Structure–Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c01349#.Y1QSx2sYlhs.twitter

@APermeation Analysis of Orthogonal Efflux and Permeation Properties of Compounds Leads to the Discovery of New Efflux Pump Inhi… https://pubmed.ncbi.nlm.nih.gov/36070489/

Making sense of drug-efflux transporters in the physiological environm... https://www.sciencedirect.com/science/article/pii/S1369527422000637

We developed and validated a method to analyze compounds accumulation in difficult bacteria: Property space mapping of Pseudomonas aeruginosa permeability to small molecules https://pubmed.ncbi.nlm.nih.gov/35581346/

A new database for antibiotics - AB-DB: Force-Field parameters, MD trajectories, QM-based data, and Descriptors of Antimicrobials. Sci Data 9, 148 (2022). https://doi.org/10.1038/s41597-022-01261-1

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