Nathaniel Martin (Pharmaceutical Sciences) has been awarded a ZonMw grant of 500,000 Euros to study drug-resistant Gram-negative bacteria. The Martin group will pursue new methods of sensitizing Gram-negative pathogens to antibiotics that are typically only active against Gram-positive strains. Gram-negative bacteria have an extra layer of protection against drugs: an additional outer membrane, which forms a physical barrier for antibiotics that target the bacterial wall. To overcome this barrier, the researchers will investigate a variety of “two-step” approaches, combining antibiotics with other drugs that can disrupt the outer membrane. Martin: “Basically, it means that we need to be more strategic in our approach.”
The threat of drug-resistant bacteria is getting worse. Earlier this month, an American woman died of a Gram-negative bacterial infection that turned out to be resistant to all 26 antibiotics that were available to the doctors treating her. Working together with Suzan Rooijakkers (UMC Utrecht) and Oscar Kuipers (University of Groningen), partners in the granted ZonMw project, Martin will investigate different combinations of drugs that could work in synergy to kill such drug-resistant Gram-negative pathogens.
“In the process, we want to change the way antibiotics are screened,” explains Martin. “Current testing methods are not representative of the human body: they discount the fact that human blood contains proteins that can disrupt the outer membrane of Gram-negative bacteria.” Rooijakkers and her group are experts in studying how such proteins function. Working together, Martin and Rooijakkers will systematically evaluate the effects of blood components on the in vitro tests used to evaluate antibiotic activity. “Such approaches may help catch effective drugs that we would otherwise have missed using conventional screens. We hope to bring a revolution to in vitro lab testing.”
The collaboration was formed within one of the research themes of the Netherlands Centre for One Health (NCOH). In the Martin and Rooijakkers labs in Utrecht, researchers will use high-throughput tests to identify possibly interesting combinations of drugs. The group of Oscar Kuipers in Groningen will in turn investigate how such combinations may limit heteroresistance: a phenomenon in which certain bacteria are not affected by antibiotics, even though they are genetically identical to other bacteria, which are affected. This may give insight into the processes leading to antibiotic resistance.
In addition to the researchers from Utrecht University, UMC Utrecht, and the University of Groningen, Martin’s spin-off company Synamp Pharmaceuticals BV is also involved. Martin explains: “If our research produces new products that show clinical relevance, it is important that there are companies interested in doing further development work.” However, there are other types of outcome that Martin would also be happy with. “Another type of outcome can be knowledge, such as identifying a promising combination of an existing antibiotic with another approved drug. In such cases clinicians may be able to start using that combination right away.”