Dr Ashraf Zarkan

Biography

Ash is a Transition To Independence Fellow (funded by the Rosetrees Trust, the Isaac Newton Trust, and the School of Biological Sciences at the University of Cambridge). Ash has a BSc in Pharmacy, an MSc in Medical Microbiology and a PhD in Biochemistry. Before starting his fellowship, he trained in the labs of Dr Hee-Jeon Hong, Prof Martin Welch and Prof George Salmond (as PhD 2012-2016, Department of Biochemistry, University of Cambridge, UK) and Dr David Summers (as PostDoc 2016-2022, Department of Genetics, University of Cambridge, UK).

Research

Serious bacterial infections represent an unprecedented worldwide threat, due partially to the emergence of antibiotic-resistant bacteria for which we have limited therapies. Antibiotic resistance is on the rise and has been identified as one of the World Health Organization’s global health challenges in the next decade. It is estimated that unless action is taken, the burden of deaths from antibiotic resistance could reach 10 million lives each year by 2050, with a cumulative cost to global economic output of $100 trillion. On a more positive note, multiple global efforts have been initiated recently to encourage the development of antibiotics, such as the ‘subscription-style’ antibiotic payment model in the UK and the PASTEUR Act in the US.

A key aspect of the antibiotic resistance problem is the ability of bacteria to form biofilms, which provide protection from both antibiotics and the host immune system. Biofilms are implicated in chronic infections such as tuberculosis, cystic fibrosis-associated lung infections and urinary tract infections (UTIs). Another key aspect of antibiotic resistance is the ability of sub-populations (<1%) of genetically sensitive bacterial cells, known as persisters, to survive antibiotic treatment by entering a dormant or semi-dormant state. After treatment finishes, persisters can resume growth, leading to infection recurrence such as often seen in UTIs. In addition to the above problems with the pipeline of new antibiotics, we do not yet have a solution to the problem of persisters and biofilms, even with existing antibiotics that do have efficacy.

UTIs are among the most common bacterial infections, affecting 150 million people per year worldwide and 75% of infections are due to uropathogenic E.

coli . UTIs are highly prevalent in women, affecting an estimated 50% in their lifetime. A major problem with UTIs is recurrence of infection associated with the ability of E. coli to form biofilms harbouring persisters on the bladder lining or on indwelling catheters. There is an urgent need for innovative treatments to combat bacterial biofilms and persisters, especially in UTIs.

Our work seeks to understand the mechanisms of biofilm and persister formation in E. coli. The goal is to develop new therapies to inhibit E. coli biofilms and persisters, thereby reduce pathogenicity, improve antibiotic effectiveness and reduce recurrency in UTIs.

Publications

Key publications:

1. Goode, O., Smith, A., Zarkan, A, et al (2021). Persister E. coli have a lower intracellular pH than susceptible cells but maintain their pH in response to antibiotic treatment. mBio 12:e00909-21. https://doi.org/10.1128/mBio.00909-21

2. Zarkan, A, et al (2020). Inhibiting indole signalling offers a potential strategy for combatting antibiotic persisters. Behind the Paper: Nature Microbiology Community. https://go.nature.com/2ZkGaFx

3. Zarkan, A, et al (2020). Inhibition of indole production increases the activity of quinolone antibiotics against E. coli persisters. Scientific Reports 10:11741. https://doi.org/10.1038/s41598-020-68693-w

4. Zarkan, A., et al (2020). Local and Universal Action: The Paradoxes of Indole Signalling in Bacteria. Trends in Microbiology 28:566-577. https://doi.org/10.1016/j.tim.2020.02.007

5. Zarkan, A., et al (2019). Indole Pulse Signalling Regulates the Cytoplasmic pH of E. coli in a Memory-Like Manner. Scientific Reports 9:3868. https://doi.org/10.1038/s41598-019-40560-3

6. Zarkan, A., et al (2017). Zn(II) mediates vancomycin polymerization and potentiates its antibiotic activity against resistant bacteria. Scientific Reports 7:4893. https://doi.org/10.1038/s41598-017-04868-2

7. Zarkan, A., et al (2016). The frontline antibiotic vancomycin induces a zinc starvation response in bacteria by binding to Zn(II). Scientific Reports 6:19602. http://doi.org/10.1038/srep19602

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