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

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

Infectious diseases constitute one of the highest causes of deaths of human beings throughout the world, by the millions every year. The World Health Organization (WHO: www.who.int/research/) stated that 'deaths from acute respiratory infections, diarrhoeal diseases, measles, AIDS and malaria account for more than 85% of the mortality from infection worldwide' (WHO Reports 2010 and . The total amount of children died under 5 years of age in 2012 summed up to 6.6 million worldwide, and nearly 60% of these deaths were due to infectious diseases. Pneumonia is the largest single cause of death in under-fives and about 80% of them could be cured by prevention and proper antibiotic treatment. These figures apply mostly for the under-developed countries. In developed countries, albeit the rates of mortality are much lower, there is high-risk populations formed by children, elderly and immuno-compromised people, which are generally subjected to antibiotic treatments, either ambulant or in hospital. The problem can be much bigger than envisaged with the appearance of bacteria exhibiting multi-or even pan-drug resistance (Falagas and Karageorgopoulos 2008) , or the recent epidemics outbreak of viral infections like Ebola, avian influenza and Middle East respiratory syndrome (http://www.cdc.gov/outbreaks/). Thus, the global figure of people suffering from microbial infections may reach the hundreds of millions. This poses huge ethical, medical and economical concerns that must be tackled in the most urgent way. One of the main problems found in the everyday practice of treating these patients is the steady emergence of multidrug-resistant bacteria. This problem dictates the need for major efforts to discover new classes of antimicrobial drugs. The current portfolio of compounds in clinical trials includes mostly derivatives of existing antibiotics for which underlying resistance mechanisms already exist (WHO, Global report on antimicrobial resistance 2014; http://www.who.int/drugresistance/documents/ surveillancereport/en/). This scenario is particularly worrisome in the case of hospital infections caused by highly resistant pathogens, although some advances have been achieved (Bassetti et al., 2013) . Antibiotic resistance (AbR) is not a new conundrum and it seems that there is no ultimate denouement but just a temporary regime to alleviate the problems. The emergence of resistance to the few antibiotics that are still useful for the treatment of nosocomial infections, as well as the knowledge accumulated on the mechanisms of action of antibiotics (Blair et al., 2015) , urges the need for novel infection prevention and control strategies (Table 1 ).