Neisseria gonorrhoeae *Ketol-Acid Reductoisomerase Is a Potential Therapeutic Target DOI: http://dx.doi.org/10.5772/intechopen.107993*

or destruction of antimicrobials [13]. As an example, gonococcal resistance to penicillin and tetracycline is due to the mutation of *blaTEM* gene and the *tetM* [16]*,* respectively, which are plasmid-borne and can be easily transferred.

AMR genetic determinants are chromosomally transcribed where some can provide high resistance levels *in vitro* and *in vivo* leading to treatment failure. The acquisition of a single AMR determinant could confer only a cumulative increase in AMR compared to the cumulative effect of certain AMR determinants. The interaction between them may result in a significant increase in AMR levels. For example, the development of several chromosomally inserted determinants results in the resistance of *N. gonorrhoeae* to penicillin.

This looming health threat has restimulated interest in the development of new antimicrobial therapies. Active efforts are being made by several pharmaceutical majors to identify the drug targets and develop new drugs to treat such diseases effectively [17]. These targets should be present in microbes and plants, but not in humans.

Based on previous studies, the branched-chain amino acid (BCAA) pathway has been considered an attractive target for antimicrobial drug discovery as a result of comparative pathway analysis between host and pathogen [17]. First, it has been shown that all enzymes in the pathway are essential for the growth of bacteria in culture. Second, this pathway is present only in bacteria, plants, and fungi but not in animals and humans. Hence, inhibitors that target these enzymes are likely to be nontoxic to humans [18].

The BCAA pathway I is responsible for the synthesis of Leucine, valine, and isoleucine. However, this metabolic pathway is absent in humans and other animals, making them unable to synthesizee their own BCAAs and rely on obtaining these essential nutrients from their diet. Consequently, BCAA enzyme inhibitors are likely to be effective drugs, while not exerting any toxic effects in humans [1]. Ketol-acid reductor-isomerase (KARI) is the second enzyme in the branched-chain amino acid (BCAA) biosynthesis, which regulates many physiological activities in a variety of organisms from bacteria to fungi and plants. The conservation in fungi but absence in mammals of the BCAA biosynthetic pathway makes it the target for herbicides, fungicides, and antimicrobial compounds [19]. KARI catalyzes the conversion of 2-acetolactate and 2-aceto-2-hydroxybutyrate to 2,3-dihydroxyisoverate and 2,3-dihydroxy-3-methyl valerate, respectively. ILVC is a bifunctional enzyme that catalyzes two quite different reactions, but occurs at a common active site, acting both as an isomerase and as a reductase [19].

Previous studies showed the efficiency of some KARI inhibitors against *S. aureus*, *M. tubercul*osis with an inhibitory effect on bacterial growth leading to the killing of bacteria [1, 20]. By assessing the presence of the KARI enzyme in pathogens and understanding its structure and draggability, the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally.

This review focuses on looking for the presence of the KARI enzyme among pathogens, bacteria, and fungi, the study of its expression and production during the host infection, and its common druggable site and susceptibility to previously recommended enzyme inhibitors.
