A novel STK1-targeted small molecule as an "antibiotic resistance breaker"

Inh2-B1 serves as a therapeutically important “antibiotic-resistance-breaker,” which enhances the bactericidal activity of Ceftriaxone/Cefotaxime against highly pathogenic MDRSA infection.

The Need

Highly pathogenic and multidrug-resistant Staphylococcus species encompasses methicillin-resistant strains of S. aureus (MDRSA) and S. epidermidis (MDRSE) that have developed resistance to multiple traditional antibiotics, including the 5th generation cephalosporin (Ceftaroline). Because of the recent emergence of antimicrobial resistance, biofilm-forming MDRSA and MDRSE have been commonly incriminated in a variety of invasive infections of the bloodstream and surgical site at a much higher frequency..

The use of antibiotics in food has also resulted in faster mutations of S. aureus, exacerbating this burgeoning issue. Additionally, both small and large companion and livestock populations have been problematic for both the animals as well as immuno-deficient humans in contact with them..

Given the lag in development of newer antibiotics, emerging multidrug-resistant traits in the bacterial strains warrants a more urgent need to identify new agents for effective treatment of MDRSA/MRSE infections. Recent findings suggest that S. aureus serine/threonine kinase STK1 may serve as a target for the development of a novel targeted therapeutic that permits physicians to use on the market antibiotics to treat antibitotic-resistant bacterial and disrupt MDRSA biofilms.

The Technology

Researchers at The Ohio State University, led by Dr. Vijay Pancholi, have discovered novel small molecule quinazoline derivatives (Inh2-B1) that can be combined with cephalosporins such as Ceftriaxone (CFTX) and Cefotaxime (CFT) to inhibit MDRSA/MRSE infection. Inh2-B1 inhibits the kinase activity by directly binding to the catalytic domain of Ser/Thr protein kinase (STK1). Inh2-B1 causes none to minimal cell-dependent toxicity to human cells and enhances the bactericidal activity of beta-lactam antibiotics, Ceftriaxone and Cefotaxime, against MDRSA both in vitro and in vivo. Inh2-B1 also disrupts MDRSA biofilms and increases the bactericidal activity of oxacillin, nafcillin and cephalosporins. Thus, combination therapy utilizing Inh2-B1 as an "antibiotic-resistance breaker" with Ceftriaxone/Cefotaxime results in a more effective treatment against MDRSA/MDRSE infections by disrupting biofilms and by augmenting the bactericidal activity of cephalosporins.

Commercial Application

  • Pharmaceutical development
  • Drug-resistant disease treatment methodology
  • New treatments for MDRSA/MDRSE

Benefits/Advantages

  • MDRSA/MDRSE growth inhibited
  • Minimal toxicity to normal cells
  • Disrupts MDRSA/MDRSE biofilm formation
  • Enhances efficiency of common antibiotic agents

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