Dr Michaela Serpi

Publication

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Research

Antibacterial

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.

This work was funded by a ISSF3 wellcome trust cross disciplinary award in collaboration with Prof David Williams at the School of Dentistry and Dr Ian Fallis at the School of Chemistry at Cardiff University.  A GW4 Seed award has allowed to expand the collaboration to Dr Maisem Labei at Bath University, Dr Seana Duggan at Bristol university and Dr Dhara Malavia and Dr Mark Stappers at Exeter University.  Prof Laura De Luca at Messina university is also supporting the project with computer-aided drug design tecniques.

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. I am currently exploring the potential of old nucleosides and their new analogues to fight antimicrobial resistance.

This work is in collaboration with Dr Mandy Wootton, Lead Scientist at the Specialist Antimicrobial Chemotherapy Unit at Microbiology Cardiff and with Dr Hans Steenackers from Centre of Microbial and Plant Genetics, Heverlee, Belgium.

Lysosomal storage disorders

These are rare genetic metabolic disorders due to defects in lysosomal functions, usually apparent from infancy with some children having serious life-threatening medical problems. Together with Dr Emyr Lloyd-Evans, a sphingolipid-expert biologist at the School of Biosciences of Cardiff University we are working at the development of analogues a natural compound capable to inhibit the glucosylceramide synthase, an enzyme involved in the Gaucher disease. Together with Dr Fabrizio Pertusati and Dr Emyr Lloyd-Evans we are also looking at new versions of the drugs cysteamine and miglustat, which will be more effective and safer medicines for the treatment of two rare and genetic, life-threatening conditions respectively cystinosis and Nieman Pick disease. A Wellcome Trust ISSF3 grant (49k) is currently supporting the research for the cystinosis.

This research is conducted in collaboration with Dr. Lloyd-Evans at the Cardiff School of Bioscience and Dr Fabrizio Pertusati at the Cardiff School of Pharmacy.

Anticancer

In collaboration with NuCana, a clinical-stage biopharmaceutical company  I use the ProTide technology to transform some of the most widely prescribed chemotherapy agents, nucleoside analogs, into more effective and safer medicines. ProTide-type anticancer agents overcome the key resistance mechanisms associated with nucleoside analogues enhancing their effectiveness in the cancer therapies. Other than developing new anticancer drugs we have established a research network with Professor David Harrison at the School of Medicine of St Andrew University and Professor Chris Pepper at Brighton and Sussex Medical School  to investigate the biological and biochemical mechanism behind the improved activity of the phosphoroamidate prodrugs.

Biography

I graduated in Pharmaceutical Sciences in 1998 from Cagliari State University. After a brief traineeship at Rhone Poulenc Rorer in the Research Centre of Vitry Alfortville in Paris (FR) in 2000 I was awarded a Glaxo Welcome Fellowship to join the research group of Professor Roberto Pellicciari at the University of Perugia (Italy) where I completed my PhD in Medicinal Chemistry in 2005 with a research directed to the neurodegenerative field and in collaboration with the pharmaceutical company Lundbeck in Copenhagen (DK). During my PhD I was awarded with a Marie Curie Training Site Fellowship, which gave me the opportunity to spend six months working at the Royal Danish School of Pharmacy in Copenhagen (DK). In 2005 I then joined the medicinal chemistry group of Professor Chris McGuigan at Cardiff University working until January 2008 as post-doctoral on the carbohydrate chemistry of N-acetyl glucosamine analogues for an osteoarthritis drug discovery project sponsored by the pharmaceutical company Bioberica. From January 2008 to January 2011 I have worked at the design of acyclic nucleoside phosphonate analogues for the treatment of viral infections as a post doctoral fellow funded by NIH at the University of Southern California (LA, USA) in the Group of Professor Charles E. McKenna. In 2011 I was back at Cardiff University working as Research Associate first for an antiviral project funded by Inhibitex/BMS (2011-2012) and then as Research Fellow for an oncology programme sponsored by NuCana. In October 2020 I was appointed as lecturer in medicinal chemistry at the School of Chemistry of Cardiff University.  My research interest covers different areas of drug discovery such as the development of anticancer and antimicrobial agents, as well as of small molecules for the treatment of rare diseases.