?A small couple for the big-three? (Two4Three) is an innovative and ambitious project where we propose to fight Malaria, Tuberculosis (TB), and HIV-1/AIDS (HIV) using Ionic Liquids (IL).
One of the major societal challenges today is the increasing resistance of pathogens against available drugs, a matter of great concern for the ?Big Three Diseases? (BTD) ? malaria [1-3], HIV [4, 5], and TB [6], according to the WHO. These diseases often emerge as co-infections, especially in Africa, but enduring in a never-ending search for the next first-line multi-target drug no longer seems a sustainable approach, as suggested by recent news:
-Malaria, wiped out in U.S., still plagues American travelers (http://bit.do/malariaUS)
-Malaria drugs fail for first time on patients in UK (http://bit.do/malariaUK)
-EU Leaders Urge Funding of Critically-needed New Tools against Drug-resistant Tuberculosis  (http://bit.do/TBresist) HYPERLINK "http://bit.do/malariaUS"
-TB/HIV outreach finding patients in remote South Africa (http://bit.do/tbhiv)
-TB/HIV co-infections up 40% across Europe over the last five years (http://bit.do/euroTBHIV)
We intend to address this problem from a completely new perspective: combine known drugs to form IL active against HIV/TB, TB/malaria, malaria/HIV co-infections (Fig. 2). [3, 7] Such IL will act as new formulations potentially exhibiting dual action, while possessing physico-chemical properties favoring oral bioavailability, more potent activity, and absence of resistance.[3] In fact, the physico-chemical and biopharmaceutical properties of ionizable drugs are influenced by the selected counter-ion. In other words, pairing of ionizable drugs with convenient counter-ions offers a means to modulate pharmacokinetics, especially at the absorption and membrane permeability levels, and also pharmacodynamics. This may help to circumvent some drug-related challenges, as poor oral bioavailability, toxicity, or even polymorphism issues.[9] In this connection, our recent work highlights the promising properties of drug-based IL, by having developed ampicillin-derived IL active against resistant bacteria,[9] and primaquine-based IL active against the three stages of malarial infection in the human host (Fig. 2).[3]
With this new project, we wish to demonstrate that development of drug-based IL must be pushed forward, both because it will favor the recycling of many drugs currently put on hold due to resistance and/or bioavailability issues [10], and because novel ionic structures can be envisaged where a cationic drug (e.g., an antimalarial) can be paired with an anionic one (e.g., an antiretroviral) to produce organic salts as low cost dual-function drugs. This is our working hypothesis which, if proven correct, will open brand new avenues towards cheap and effective dual-action medicines against the BTD. In other words, this is a low-cost innovative approach that may yield a major advance in the control of the most concerning infections of today.