New Weapon for Fighting Antibiotic Drug Resistance

The most important antibiotics in general use today are the b-lactam family of products, but the medical community faces a serious problem with these antibiotics: the increasing development of drug resistance. The resistance is caused by hydrolysis of the b-lactam by a bacterial lactamase enzyme, but fortunately it can often be overcome by the use of a serine b-lactamase inhibitor in combination with the drug. This approach is successfully used already, for example clavulanic acid is used in combination with amoxycillin in Augmentin.

Unfortunately, various b-lactam drugs are also inactivated by metallo-b-lactamases, which cannot be overcome by the current range of serine b-lactamase inhibitors. Until recently, there have been no metallo-b-lactamase inhibitors of any kind to protect the drugs from this type of resistance.

Researchers at Oxford University’s Department of Chemistry now believe they have found a solution to this problem. They have discovered a new class of inhibitors of Class B bacterial lactamases, which are responsible for the hydrolysis of many antibiotics and hence drug resistance in those bacteria.

The researchers identified a number of potentially useful inhibitor compounds, which are mainly perfluoroalkyl derivatives of a-amino acids or a peptide, made by either conventional routes or by a novel method involving oxazolidinone formation, silylation and desilylation with ring cleavage. Assays for inhibition were carried out using the published procedures of Walter et al to yield inhibition constants, and kinetic data is also available for certain compounds.

The new metallo-b-lactamase inhibitors provide an attractive alternative approach to enhancing antibiotic performance and overcoming antibiotic resistance in bacteria.

Isis Innovation, Oxford’s technology transfer company, holds a granted patent on this novel technology and welcomes contact from companies interested in commercially developing this technology for the drug industry.

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