Overcoming drug resistance in multi-drug resistant cancers and microorganisms: a conceptual framework.

Resistance development against multiple drugs is a common feature among many pathogens--including bacteria such as Pseudomonas aeruginosa, viruses, and parasites--and also among cancers. The reasons are two-fold. Most commonly-used rationally-designed small molecule drugs or monoclonal antibodies, as well as antibiotics, strongly inhibit a key single step in the growth and proliferation of the pathogen or cancer cells. The disease agents quickly change or switch off this single target, or activate the efflux mechanisms to pump out the drug, thereby becoming resistant to the drug. A second problem is the way drugs are designed. The pharmaceutical industry chooses to use, by high-throughput screening, compounds that are maximally inhibitory to the key single step in the growth of the pathogen or cancer, thereby promoting selective pressure. An ideal drug would be one that inhibits multiple steps in the disease progression pathways with less stringency in these steps. Low levels of inhibition at multiple steps provide cumulative strong inhibitory effect, but little incentives or ability on the part of the pathogen/cancer to develop resistance. Such intelligent drug design involving multiple less stringent inhibitory steps is beyond the scope of the drug industry and requires evolutionary wisdom commonly possessed by bacteria. This review surveys assessments of the current clinical situation with regard to drug resistance in P. aeruginosa, and examines tools currently employed to limit this trend. We then provide a conceptual framework in which we explore the similarities between multi-drug resistance in pathogens and in cancers. We summarize promising work on anti-cancer drugs derived from the evolutionary wisdom of bacteria such as P. aeruginosa, and how such strategies can be the basis for how to look for candidate protein/peptide antibiotic drugs from bioengineered bugs. Such multi-domain proteins, unlike diffusible antibiotics, are not diffusible because of their large size and are often released only on contact with the perceived competitor. Thus, multi-domain proteins are missed during traditional methods of looking for growth zone inhibition of susceptible bacteria as demonstrated by antibiotics, but may represent the weapons of the future in the fights against both drug-resistant cancers and pathogens such as P. aeruginosa.