The 2014 World Health Organization’s report on Antibiotic Resistance revealed that this phenomenon is spreading across the world and it is threatening the effective prevention and treatment of common infections caused by bacteria, parasites, viruses and fungi. It has been estimated that if no concerted effort to discover and develop new antibiotics will be made by all countries, by 2050 the number of deaths per year due to antibiotic-resistant infections will reach 10,000,000 with an associated cost to the global economy of $1 trillion.
The long-term goal of this project is to find new-targeted treatments for infections caused by antibiotics-resistant bacteria strains.
Among drug resistant gram-positive bacteria, Staphylococcus aureus, which is responsible for skin and soft tissue infections and bacterial sepsis, is perhaps the pathogen of greatest concern. The mortality of S. aureus bacteremia remains approximately 20–40%. S. aureus is increasingly resistant to a greater number of antimicrobial agents (e.g. methicillin-resistant strain (MRSA)). The glycol-peptide antibiotic vancomycin is often seen as a last resort to treat such infections; however, strains with vancomycin resistance (VRE) have already been reported. Due to the increasing difficulty in treating these infections new ways of inhibiting the growth of S. aureus and other bacteria strains (e.g. MRSA, C. difficile, Enterococcus faecalis, etc.) are heavily sought after. For this we are investigating small drug molecules as potential inhibitors of the synthesis of Lipoteichoic acid. Two enzymes are the specific targets:
1) the lipoteichoic acids synthase (LtaS), a key enzyme involved in the synthesis of type I LTA the synthesis of (LTAs), which are glycol-polymers that functionalize the peptidoglycan in gram positive organisms. LTAs are essential for the growth of gram-positive bacteria.
2) D-alanyl carrier protein ligase (AMP forming) (DltA), which is one of the enzyme involved in the functionalization of LTA with D-alanine. Blocking the D-alanylation process, leads in many pathogenic bacteria to a higher susceptibility to cationic antibiotics and an increased host defenses. Lack of D-alanine also abolishes biofilm production and reduces pathogenicity of these bacteria.
We are also interested in repurposing nucleoside drugs as antibiotic. Specifically Nucleoside analogues used in the treatment of viral infections and cancer conditions have been shown to also have some effect against bacteria. In particular numerous natural nucleosides and their synthetically modified analogues have been reported to have moderate to good antibiotic activity against different bacterial and fungal strains. These compounds target several crucial processes of bacterial and fungal cells such as nucleoside metabolism and cell wall, nucleic acid, and protein biosynthesis. Therefore, they have a great potential to be used as antibiotics for the treatment of bacterial infections, especially those caused by multi-resistant bacterial strains.
Novel antibiotics are urgently needed to combat the rise of infections due to drug-resistant microorganisms. We currently exploring the potential of nucleoside and their new analogues to fight antimicrobial resistance.
Dr Mandy Wootton, Lead Scientist at the Specialist Antimicrobial Chemotherapy Unit at Microbiology Cardiff.
Professor David Williams, Professor of Oral Microbiology, School of Dentistry, Cardiff University.