Microorganisms have always been able to develop resistance to antibiotic through various mechanisms, however, this process has been hugely accelerated by their misuse and overuse in particular in controlling bacterial infection in intensive animal farming. This has recently culminated with the isolation of bacterial strains resistant to colistin, an antibiotic used as a last resort for life-threatening infections. The WHO issued several warnings, however no strict actions were undertaken, and as a consequence we are getting closer to a point of no-return, the so called post-antibiotic era.
Antibiotic resistance is now a major issue for public health and is leading to increased mortality (>50000 in Europe and US alone every year), longer hospital stays and as a consequence having a huge impact on national health care budgets. If no action is taken, it is estimated that by 2050 10 million people worldwide will die every year from antibiotic resistant bacterial infections. Despite the urge for new and efficacious antibiotics able to fight resistant bacterial strains, only two new classes of antibiotics have reached the market in the last thirty years.
Why is it so difficult to develop antibiotics with a novel mechanism of action? There are two main reasons why pharmaceutical companies are not developing new antibiotics: one is economical (low investment return) as the newly approved drugs will be used only against multi-resistant strains (small number of patients); and the second is technical (identification of new targets and chemical matter), has proven to be quite challenging. Genomics have allowed the identification of new validated targets to start antibacterial drug discovery programs, with >60 targets being screened by 34 companies. A huge effort was made by GSK (running 70 HTS screens) and AstraZeneca (running 65 HTS screens), which have led to the identification of very few lead series. However, the biochemical activity of these compounds was not translated in cellular assays, with potential antibiotics not being able to penetrate across the bacterial membrane. One of the main reasons behind this attrition is down to physicochemical properties of the chemical libraries used, which nowadays are finely honed to follow Lipinski’s rule of five, rules that are not strictly followed by antibiotics.
In this context, Innovative Medicines Initiative (a partnership between the European Union and the European Federation of Pharmaceutical Industry and Associations) has launched a €700 million programme “New Drugs 4 Bad Bugs” to tackle antimicrobial resistance as a collaboration between industry, academia and biotech organization. Of particular interest from an early stage drug discovery point of view, are the projects TRANSLOCATION (Molecular basis of the bacterial cell wall permeability), aimed to better understand the complex machinery behind drug transport and efflux in gram-negative bacteria; and ENABLE (a drug-discovery platform for antibiotics) aimed at lead-optimisation of promising compounds and progressing them into drug candidates. The aim is to progress at the least one compound into phase 1 clinical trials by 2020. Other projects that are part of this programme include: COMBACTE (creating a pan-European network of clinical sites), COMBACTE-CARE (taking on the most dangerous resistant bacteria), COMBACTE-MAGNET (help on healthcare-associated infections), iABC (new treatments to help cystic fibrosis patients), DRIVE-AB (New economic models for antibiotic development). In 2015, the Centers for Disease Control and Prevention (US) has launched their strategy to combat antibiotic resistance (National Strategy for Combating Antibiotic-Resistant Bacteria (CARB))
Several initiatives and research programmes are currently trying to solve this antibiotics crisis; in the meantime the WHO provides guidelines on how everyone in society, from the general public to doctors, pharmacists, veterinarians and farmers, can help to slow down the process of antibiotic resistance.
Blog written by Marco Derudas