By Mili Jayadeep | Science Editor
Ever since the discovery of the first antibiotic in 1928 by Alexander Fleming, the challenges for treating infectious diseases were largely overcome. Antibiotics were seen as the miracle drug, which revolutionised medicine. Due to the inappropriate use of antibiotics, bacteria have developed resistance towards them thus rendering many antibiotics useless against the resistant bacterial strains. The World Health Organisation (WHO) says that antibiotic resistance is among the top ten public health threats against humans. A government report predicts that deaths due to multiple-drug resistance may reach upto 10 million by 2050 if unnecessary antibiotic use continues. This increasing problem is putting a great amount of pressure for the search for new classes of antibiotics. Therefore any progress in this area of research is promising for combating this growing problem.
A team of scientists at Wistar Institute have discovered a new class of drugs that elicits a fast immune response as well as target drug resistant bacteria. Their findings were published in the journal, Nature. The lead author of the study and assistant Professor in the Vaccine & Immunotherapy Center, Farokh Dotiwala says,
“We took a creative, double-pronged strategy to develop new molecules that can kill difficult-to-treat infections while enhancing the natural host immune response”
Current antibiotics aim to interfere with bacterial functions such as protein and nucleic acid synthesis, cell membrane formation and metabolic function. However, mutations can develop over time in these bacteria resulting in antibiotic resistance, which results in antibiotic ineffectiveness. Dotiwala describes,
“We reasoned that harnessing the immune system to simultaneously attack bacteria on two different fronts makes it hard for them to develop resistance.”
The researchers looked at an enzyme called IspH involved in a metabolic pathway crucial for bacterial functioning known as the methyl-D-erythritol phosphate (MEP) pathway. This pathway has involvement in the synthesis of isoprenoids, which are found in bacteria responsible for cell function. As this pathway was not present in humans but very prevalent in a variety of different bacteria, this made it an ideal treatment approach. Using computer modelling, the team screened molecules that inhibited the IspH enzyme and chose some molecules to begin with. Collaborating with Wistar’s medicinal chemist, Joseph Salvino, Professor in The Wistar Institute Cancer Center and a co-senior author on the study enabled them to choose molecules able to enter the bacterial cell for greater potency.
Their findings from experimenting on antibiotic resistant bacteria showed the superior effects of the new compounds when compared to traditional antibiotic compounds. Testing on human cells also confirmed the non-toxicity of these molecules. Kumar Singh, Dotiwala lab postdoctoral fellow and first author of the study says,
“Immune activation represents the second line of attack of the DAIA strategy.”
Dotiwala is also optimistic about their findings:
“We believe this innovative DAIA strategy may represent a potential landmark in the world’s fight against AMR, creating a synergy between the direct killing ability of antibiotics and the natural power of the immune system.”
The preliminary work done by these researchers are of great importance in the search for solutions to combat antibiotic resistance. With further research and trials, these compounds have the potential to contribute to treatments for antibiotic resistant bacterial infections.