Ryan Altman photoRyan Altman
Assistant Professor
Department of Medicinal Chemistry
University of Kansas

 

Inhibition of Bacterial Resistance Enzymes using Structure-guided Drug Design (2016-2017)

Susceptible bacteria acquire clinical resistance to aminoglycoside antibiotics by expression of resistance enzymes that modify and deactivate the drugs. The present application aims to overcome bacterial resistance to aminoglycosides by developing inhibitors of these resistance enzymes in Gram + microorganisms.  Antibiotic resistance is one of the three greatest threats to human health, and efforts to combat antibiotic
resistance are essential for the long-term viability of humankind. On strategy to circumvent resistance involves inhibition of bacterial resistance enzymes, which can restore efficacy of approved antibiotics, as has been demonstrated for the beta-lactam antibiotics. In similar fashion, the current application aims to develop modulate bacterial resistance to FDA-approved aminoglycosides (AGs) antibiotics by developing small molecule inhibitors of a key bacterial resistance enzyme that is disseminated throughout multidrug-resistant Gram + bacteria. To accomplish this general goal, the present research plan aims to 1) employ a structure-guided design approach to synthetically elaborate lead fragments that bind to the bacterial resistance enzyme. and 2) establish translational relevance of lead inhibitors using clinically-employed assays.

Inhibition of Bacterial Aminoglycoside Resistance Enyzmes using a Fragment-based Drug Design Approach (2015-2016)

Antibiotic resistance is one of the three greatest threats to human health, and efforts to combat antibiotic resistance are essential for the long-term viability of humankind. Aminoglycosides (AGs) constitute one class of FDA-approved antibiotics that are indicated for severe infections caused by Gram + and Gram – microorganisms (MOs), many times in combination with cell-wall active agents. However, resistance to AGs is currently a major problem, and has rendered several members of the class obsolete. Resistance to AGs has been partially attenuated by the development of new agents; however, resistance to AGs is rising clinically, mainly due to aminoglycoside modifying enzymes (AMEs) that modify the drugs, which blocks the ability of the drug from acting at its target. The present proposal aims to develop agents that inhibit the critical AME for Gram + MOs, thus resorting bacterial susceptibility to AG antibiotics.

To accomplish this general goal, the present research plan aims to: 1) identify lead inhibitors of a key bacterial resistance enzyme in Gram + MOs using a fragment-based drug design (FBDD) approach, and 2) establish translational relevance of lead inhibitors using clinically-employed assays.