In recent years, there has been an intensive search for antimicrobial agents which are effective against bacterial resistant to multiple antibiotics. We have been involved in developing a novel class of bacterial inhibitors, the biphenyl esters of trans-4-guanidinomethylcyclohexane-carbolic acid, where individual compounds exhibit differential effects against different bacterial species. We have further cloned the gene for the putative target (the PrlC proteinase) of this class of inhibitors. We believe that these compounds have significant potential for commercialization. Before proceeding to preclinical development, we propose: [1] to obtain more definitive evidence for the PrlC proteinase being the true molecular target of this class of inhibitors, knowing that target validation would facilitate subsequent structure-based modifications; [2] to establish whether bacterial strains resistant to this class of inhibitors can be isolated, before taking these compounds to the next developmental stage; [3] to identify the natural substrate of the PrlC proteinase in the bacterial cell, so as to allow the derivation of a more direct and functional surrogate endpoint for determining the activity of this class of compounds. We are confident that the experiments outlined in this proposal would yield meaningful information which will allow us to decide whether and how we should proceed, in order to bring this unique class of antibacterials to the market.
The compounds described in this application have the potential of being developed into a novel class of antibiotics against various multidrug-resistant bacteria. The proposed experiments to address the likelihood of different bacterial species establishing resistance to these inhibitors and the validation of the proposed molecular target for further structure-based modifications, are absolutely essential before proceeding to preclinical development.
