In 2013, the American Centre for Disease Control warned that humanity is approaching a “post-antibiotic era”, a time where bacterial infections become untreatable and mortality rates soar. Even today, multi-drug resistant bacteria are attributed with causing the deaths of 23,000 Americans (more than double that of gun-related homicides) and 25,000 Europeans every year.
A major problem is the lack of investment in new antibiotics. Indeed, fifteen out of the eighteen largest pharmaceutical companies have halted research in this area, and there has been no new drug class of antibiotics discovered in over forty years. However, a new study from the University of Utah has developed a method to maximise the effectiveness of antibiotics we already have, and even discovered novel antimicrobial properties of drugs not previously realised.
This method, called the overlap2 method (O2M), relies on the concept of drug synergy; when the combinational use of two drugs improves the effectiveness of both. Synergistic drug pairs are capable of killing bacteria resistant to one of the drugs in the pair, and are less likely to encounter evolutionary resistance. The O2M method aims to identify novel, synergistic combinations of antibiotics that are capable of killing multidrug-resistant bacteria.
O2M relies on already knowing at least one synergistic drug combination. A collection of mutant bacteria is grown in each of these drugs, and which mutants grow faster or slower than normal bacteria in these conditions are recorded. From this, mutants which exhibit abnormal growth in both of the drugs are identified and selected.
These selected mutants are then grown in a wide variety of other drugs to see if they also induce similar abnormal growth. If a drug does indeed affect cell growth, then this is a potential synergistic drug partner. By focusing solely on a small number of selected mutants, this methodology is far more targeted and efficient than traditional method of finding drug synergy.
Using O2M, the authors identified and validated ten novel drug synergy partners for a commonly used antibiotic, trimethoprim. One of these partners, AZT, was found to be able to synergise with trimethoprim to kill clinical isolates of pathogenic E. coli and K. pneumoniae that are resistant to trimethoprim alone. Importantly, AZT is already an FDA- and NHS-approved drug, and therefore does not require expensive clinical trials for safety testing. By studying the underlying mechanisms behind AZT and trimethoprim treatment, the authors were then able to rationally predict and confirm even more synergistic drug partners.
Thus, the O2M method provides several great advances in the field of antibacterial agents. Firstly, it identifies novel, synergistic drug combinations that are capable of treating antibiotic-resistant bacteria. Additionally, through testing only FDA and NHS-approved drugs, it can forego the need to investigate safety concerns associated with novel, individual drugs, greatly reducing the cost of clinical trials. Finally, the basic knowledge of knowing more synergistic drugs facilitates the rational design of even more combinations. Overall, the O2M method is an excellent example of using ingenuity to maximise what is already available.
This article was written by Stuart Mckellar and edited by James Hitchen.