Development of novel strategies to combat multidrug resistance mediated by efflux transporters and intracellular bacteria

<p>Multidrug resistance (MDR) is the condition where cancer cells or microorganisms cease to respond to multiple drugs. MDR conferred by efflux transporters, that deprive the bioavailability of drugs at their site of action, are a threat to cancer and malarial chemotherapy. Specifically, the mammalian ABC transporter Pglycoprotein (P-gp) has undermined many drugs in treatment of cancer and other disease states. Mutations in the parasitic transporter <em>Plasmodium falciparum</em> chloroquine resistance transporter (PfCRT) have given rise to strains unsusceptible to the aminoquionoline family of antimalarials. Using the very drug substrates, we have developed bivalent inhibitors of P-gp. Here, click chemistry has been utilized to rapidly synthesize a library of dimers based on emetine and quinine. This resulted in triazole bearing dimers that potently inhibited P-gp efflux. Bivalent quinine probes were also developed as potential mechanistic probes of P-gp. Further, the bivalent strategy was expanded to the antimalarial drugs hydroxychloroquine, quinine, mefloquine and primaquine in an effort to inhibit PfCRT. A quinine dimer, Q2, blocked PfCRT mediated efflux and successfully cleared parasitemia <em>in vivo</em> in a <em>Plasmodium berghei</em>mice model.Efforts to target pathogenic bacteria that evade antibacterial drugs by inhabiting mammalian cells will be discussed. An unnatural proline-rich peptide Fl-P_LP_RP_R-4 was developed with dual antibacterial and mammalian cell penetrating ability. Fl-P_LP_RP_R-4 was able to clear macrophages from Salmonella typhimurium and Brucella abortus infection within J774A.1 macrophage cells by 62% and 90% respectively, with no concomitant toxicity towards the host cells.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Year

2014

Author dc:creator

• Kuriakose, Jerrin

Contributors dc:contributor

• Jean A. Chmielewski
• Christine A. Hrycyna
• Mark A. Lipton
• Mathew Tantama

• Chemistry
• Organic Chemistry

Repository record dc:identifier

https://docs.lib.purdue.edu/open_access_dissertations/312

OAI identifier oai:identifier

oai:docs.lib.purdue.edu:open_access_dissertations-1397