Inhibitors of Beta Lactamase

Unmet Need
Drug resistance to antibiotics, especially β-lactam antibiotics such as penicillin, cephalosporin and related compounds is one of the most serious problems in the treatment of infectious diseases. It represents not only a significant medical problem, but a major public health and economic burden. Reports from the Center for Disease Control (CDC) indicate that hospital-associated infections (HAIs) affect 5 to 10 percent of hospitalized patients in the U.S. per year. Approximately 1.7 million HAIs occur in U.S. hospitals each year, resulting in 99,000 deaths and an estimated $20 billion in healthcare costs. Among the pathogens causing hospital-acquired infections, C. difficile (12.1%) is the leading cause followed by Staphylococcus aureus (10.7%), Klebsiella (9.9%) and Escherichia coli (9.3%).

Technology Overview
β-lactam antibiotics inhibit bacterial cell wall biosynthesis. Bacteria use several different mechanisms to escape from β-lactam antibiotics and the most widespread is the hydrolysis of β-lactams by β-lactamase enzymes. β-lactamases are endogenous bacterial enzymes that destroy β-lactam antibiotics and eliminate their efficacy.

Researchers from Johns Hopkins and Fulcrum Pharmaceuticals describe new non-β-lactam inhibitors of β-lactamases. In particular, the invention identified a novel family of low molecular weight, boronic acid-based compounds that display inhibitory activity against several β-lactamases, including versions of the enzyme that have been shown to be resistant to clavulanic acid, sulbactam and tazobactam. Antimicrobial assays indicate that these compounds are able to recover antibiotic potency in penicillin-resistant bacterial strains. These compounds are also antibacterial agents by themselves.

Chemical structures as scaffolds for the design and optimization of wide spectrum β-lactamase inhibitors have been characterized.  Each of these structures possess different positions, linking moieties, where different chemical functionalities can be introduced to optimize affinity, activity, ADME, pharmacokinetic, toxicological and other properties required for their use as orally deliverable pharmaceuticals.

Stage of Development
In vitro and in vivo data are also available.

Publications
N/A

 

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