Combinatorials

Infections with antibiotic-resistant bacteria are a major threat to public health. Due to globalisation and poor use of antibiotics, resistance is spreading rapidly. Moreover, few new antibiotics have come onto the market in the last 20 years.

Aim

In this international project, researchers have been using the latest high-throughput screens to look for new combinations of drugs that can effectively kill resistant pathogenic bacteria and to look for drugs that can prevent the spread of antibiotic resistance.

Methods

Combinations of drugs can help combat multidrug-resistant bacterial infections, but they remain largely unexplored and are rarely used in clinics. Nearly 3,000 combinations of antibiotics, human-targeted drugs, and food additives were profiled in 6 strains of three Gram-negative pathogens—Escherichia coli, Salmonella enterica serovar Typhimurium, and Pseudomonas aeruginosa—to establish general principles for antibacterial drug combinations and understand their potential.

Results

Within this project a number of important discoveries have been made and several new drug combinations have been found to be effective against multi-drug-resistant clinical strains. Furthermore, a high-throughput screen found specific inhibitors that exploit the so-called competence process in the important human pathogen Streptococcus pneumoniae. Competence allows the pneumococcus to rapidly exchange antibiotic-resistant genes with each other. In this screen we have found some potent competence blockers that are highly effective in preventing horizontal gene transfer.

Continuation

The results gained in this project now form the basis of new research and show that it is not necessarily required to discover new drugs, but that existing drugs in certain combinations can be used effectively. Future research will show whether such combinations can be successfully used in antibiotic therapy in human patients.