Metalloenzyme inhibitors for the treatment of Gram-negative bacterial infections: a patent review (2009 - 2012).

Introduction: Bacteria were divided into two main classes in consideration of their ability to retain Gram staining. Gram-positive bacteria are able to retain the blue/violet staining, whereas Gram-negative bacteria are not, as they possess a thinner peptidoglycan wall, which is surrounded by an additional outer lipopolysaccharide membrane. This constitutes a serious hurdle for antibiotics to pass through, thereby representing a mechanism of bacterial defence and drug resistance. Targeting bacterial metalloenzymes represents an attractive approach for the development of new anti-infective drugs. In particular, small molecules able to inhibit metalloenzymes are of interest for their use alone or in association with known antibiotics with the aim to reduce mutations and various drug resistance mechanisms. Areas covered: The article deals with a selection of patents claiming the use of small molecules as inhibitors of gram-negative bacterial metalloenzymes and therefore useful for the treatment of infections caused or propagated by such pathogens. Expert opinion: Inhibition of bacterial metalloenzymes from Gram-negative bacteria, such as histidinol dehydrogenase, UDP-(3-O-(R-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase, peptide deformylase, bacterial extracellular metalloprotease, and carbonic anhydrases, was reported in the scientific and patent literature. Such metalloenzyme inhibitors, amenable to the development of conceptually novel antibiotics, represent a promising approach for the development of novel anti-infectives.