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New Antimicrobial Compounds Offer Hope Against Resistant Infections
Microbes fail to develop resistance to three new potential agents in early tests
Receiving cancer therapy, having an organ transplant, or undergoing treatment for a viral disease are already serious and often frightening procedures. Suppression of the immune system, to suppress the cancer by chemotherapy or to prevent organ rejection, is often an important part of a successful recovery. But, it also leaves patients vulnerable to bacterial and fungal infections, many of which have an increasingly limited number of treatment options.
Apart from the limited treatments for the devastating effects of infections, microbial drug resistance is therefore also a problem and one we aim to help solve. In our recent paper in Bioorganic & Medicinal Chemistry, we present three new potential antimicrobial agents against which bacteria and fungi cannot develop resistance.
An Unrecognized Danger in Cancer Treatment
Society devotes considerable effort to developing treatments for diseases such as cancer, but relatively few people are aware of the high mortality rate among people who contract a drug-resistant infection while undergoing cancer treatment. The need to treat diseases like HIV and the growing use of transplantation generate another cadre of patients who also have immunosuppression and, consequently, susceptibility to infections.
These infections themselves are leading to a startling number of deaths; while doctors can try to battle infections with antibiotics, many have developed resistance and can no longer be treated. These multidrug-resistant infections are often severe or fatal in already immune-weakened patients: there were 80,000 infections of the multidrug-resistant MRSA virus in the US in 2011, leading to 650 deaths. And in individuals who contract a systemic fungal infection while being treated with immunosuppressants, mortality is as high as 30%.
Developing new antibacterial and antifungal chemical agents is thus a necessary part of the ‘war on cancer’. At the University of Kentucky, we took a holistic approach to investigating potential antimicrobial agents and we also built resistance testing into the process.
Searching for New Options
We knew that pentamidine and compounds containing hydrazine and guanidine were successful antimicrobials, and we synthesized and investigated 17 new, related compounds in the same family. We tested them all for antibacterial and antifungal activity against 11 different bacteria and seven fungi. We also tested the potential for bacteria and fungi to quickly develop resistance to these compounds.
We worked in a cycle: we synthesized new compounds, tested and re-synthesized them until we reached something with the correct balance of efficacy and lack of resistance. After each round, we assessed which aspects of the chemical’s structure – such as rigidity and hydropathy – were related to its anti-microbial activity, in order to improve the design. We also tested each compound on mammalian cells and dismissed any that might be toxic to human cells.
We found three compounds capable of attacking a large range of microorganisms and yet not inducing microbial resistance. After 15 rounds of pitting the bacterial and fungal strains against the new compounds, the microbes still failed to develop resistance.
Our results are very encouraging, as they suggest these chemical agents could form the basis of new antimicrobial drugs, with a low probability of the microbes developing resistance. We are now carrying out further tests on these three promising compounds.
The emergence of antibiotic resistance is inevitable, but the frequency and speed at which resistance develops varies from one antibiotic to another. It is critical to assess the ability of new antimicrobials to evade, as long as possible, the development of bacterial and fungal resistance early in the drug discovery process.
Read the Study
Elsevier has made the following article freely available.
Sanjib K. Shrestha et al.: “Bis(N-amidinohydrazones) and N-(amidino)-N’-aryl-bishydrazones: New classes of antibacterial/antifungal agents” in Bioorganic & Medicinal Chemistry (October 2016).
Bioorganic & Medicinal Chemistry publishes complete accounts of research of outstanding significance and timeliness on all aspects of molecular interactions at the interface of chemistry and biology, together with critical review articles. This journal is published by Elsevier.
Sylvie Garneau-Tsodikova, PhD
Sylvie Garneau-Tsodikova is an Associate Professor of Pharmaceutical Sciences at the University of Kentucky. She obtained her PhD in Chemistry in 2003 from the University of Alberta, before continuing research at Harvard Medical School and the University of Michigan as the John G. Searle Assistant Professor of Medicinal Chemistry. She is an Associate Editor for MedChemComm and on the editorial boards of Journal of Biological Chemistry and ACS Infectious Diseases. Her research focuses on understanding enzyme mechanisms involved in the biosynthesis of antibiotics and anticancer agents, and the development of new molecules to combat bacterial/fungal resistance and neurodegenerative disorders.
David Watt, PhD
Professor David Watt is a Professor in the Department of Molecular and Cellular Biochemistry. He obtained a PhD in organic chemistry from Harvard, was a postdoctoral fellow in biochemistry also at Harvard, and taught at several universities before joining the University of Kentucky. His research is focused on the synthesis of small-molecule agents for the study of interesting biological problems in collaboration with colleagues.
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