The Genomic era has led to a reductionist practice to drug discovery with an emphasis on one-disease, one-target, one-drug approach. Despite this paradigm shift from using traditional methods of drug discovery, the number of new drugs that are filed with and approved by the US Food and Drug Administration (FDA) has declined on average over the past two decades. Furthermore, it appears that the new strategies of drug discovery, which are based on high-throughput screening, combinatorial chemistry, genomics, proteomics and bioinformatics, are not bringing forth the new products that were anticipated. Knowledge of the genome sequences in humans and of various pathogenic agents has led to the identification of only a limited number of new drug targets. Moreover, there remain challenges in the development of biotechnology projects that have, to date, failed to live up to expectations, including gene therapy, stem-cell research, antisense technology and cancer vaccines. A fundamental reason for these failures likely can be explained by the fact that most of these approaches have been guided by reductionism that underestimates the complexity of biological systems and the relationships of systems between species. Most human diseases result from the interaction of many gene products, and we rarely know all of the genes and gene products that are involved in a particular biological function.

The design of the MULTIPHORE platform recognizes that most diseases are complex in nature. In the reductionist approach, the goal is to identify a drug with maximum potency at a single target. Conversely, in the MULTIPHORE approach, a drug interacts with multiple disease targets through careful incorporation of multiple pharmacophores into a single molecule or through unique combination of different mechanisms of action implicated in the disease state. The goal is not simply to maximize activity at each individual target but to identify drugs with the desired phenotype in an appropriate model or organism.

Our MDDP Platform has applicability to many disease states and as such we are using this approach to develop new agents for the treatment of infections caused by Multidrug Resistance (MDR) bacteria, ARSACS, ALS and potentially other complex neurological disorders.

The MULTIPHORE approach has general applicability to any disorder. Multidrug Resistance (MDR) in bacteria is due to adaptations in multiple bacterial systems, including enhanced drug efflux through transporters, reduction in antibiotic uptake through mutation in porins, reduction in activity through target alteration, or upregulation of alternative pathways. Mechanisms of resistance may be intrinsically genetically encoded by the bacteria or encoded on mobile genetic elements such as plasmids and transposons that allow for interspecies transfer of resistance mechanisms to different antibiotic classes. Our MULTIPHORE development candidates are designed to incorporate features that evade resistance mechanisms and/or to target multiple mechanisms of action in a single drug, enabling more effective treatment.



Figure 2. Mechanisms of resistance that reduce the activity space of antibacterial drugs



Figure 3. Properties of a Multiphore Drug designed to target MDR Pseudomonas aeruginosa