One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan, Wai Ting; Balsa, Dolors; Espinosa, Manuel

In spite of the fact that AbR compromises our ability to deal with infectious diseases, a recent report performed in the UK showed that the funds devoted to this area are small and clearly insufficient (Head et al., 2014) . Furthermore, most large pharmaceutical companies have stopped investing in new antibiotic research and development: the number of industries working on active discovery and development programs for antibacterial agents have dropped in the last 20 years from more than 20 companies to only 4 in 2013 (Shlaes et al., 2013) . In-depth analyses of the Food and Drug Administration (FDA)-approved antimicrobials have shown that the number of antibacterials attained a peak by the end of the 1990s and decreased very fast afterwards, concomitantly with the decline of pharmaceutical companies introducing new molecules with antibacterial activity into the market (Kinch et al., 2014) . Reasons for this withdrawal include that drug development is a very time consuming and costly process: from target discovery to lead compound optimization, followed by preclinical studies and final clinical development and marketing authorization can take typically more than 10 years. Thus, the pricing pressure (mostly due to the marketing of antibiotic generic compounds) and severe regulatory hurdles have accelerated the withdrawal of companies from the antibacterial drug market which, in turn, has led to the reduced number of new drugs approved by the US-FDA. The '10 × 20' initiative, launched in 2010 to promote the development of 10 new antibiotics by 2020 has resulted, so far, in only two new molecules, and the number of new drugs in the market is steadily decreasing, generating a situation that enhances the risks of returning to the pre-antibiotic era (Boucher et al., 2013) . This gloom scenario led to the proposal of rebooting the FDA's entire approach to antibiotic development (Shlaes et al., 2013) . In fact, actions in this direction have been taken by the designation of the Generating Antibiotic Incentives Now program, included in the FDA Safety and Innovation Act. This gives the FDA, through the Department of Health and Human Services, the In the case of antivirals, the discoveries paralleled those of antibiotics and, again, novel compounds have not been so frequently introduced in the market. Since antiviral drugs are highly specific for a single infectious agent, accurate diagnosis is needed before any antiviral can be prescribed, therefore limiting the number of diseases of commercial interest. The existence of effective vaccines and vaccination programs is also important to determine whether the market needs new antivirals. For instance, in the case of hepatitis B, even though an effective vaccine already exists, the number of patients already infected is still very high and they do constitute a significant population that is in need of antiviral therapy. Due to the social and economical impact, the main efforts are focused on the development of drugs against human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections (Littler and Oberg 2005) . The guidelines on the use of vaccines and antivirals especially during pandemic are very crucial. The current marketbased system does not have the capacity to supply a sudden demand of vaccine when pandemic is declared. Stockpiling of vaccines for pandemic is not practical as vaccine composition relies on the responsible virus, which can only be identified after it appears at the be