In the heyday of antibiotic development in the mid-20th century, many different chemical compounds with antibacterial properties were examined, but only a small proportion were selected for development into drugs.
But with modern-day diseases becoming increasingly resistant to those drugs, biological scientists and chemists at Leeds are now re-examining old compounds, applying advances in science and technology to test more precisely whether they could still hold the key to a future medicine.
Dr Alex O’Neill, from the Antimicrobial Research Centre at the University, said: “We’re showing the value of reviewing compounds previously put on the back of the shelf. Amongst the 3,000 or so antibiotics discovered to date, only a handful have been brought into clinical use. There may be a wealth of compounds out there with untapped potential.
“At the moment, the bugs are outsmarting the scientists, and we can’t allow that to continue. By studying compounds which past research has shown already have antibacterial properties, there is scope for a potential fast-track through the challenging early stages of drug discovery. This approach could pave the way for life-saving new drugs.”
Dr O’Neill’s latest research found that a compound identified in the 1940s could now be a realistic contender as the basis of a new antibiotic drug.
A family of compounds, known as the actinorhodins, was originally identified as having weak antibiotic properties, but was not taken forward for development into a drug.
However, Dr O’Neill said that at the time scientists did not fully differentiate the individual compounds within the family when they examined them, leading to a less than precise picture of their properties.
This prompted his team to divide the family and select a specific compound (y-ACT) for further evaluation, using an array of 21st century approaches, to assess its potential and to understand how it works against bacteria.
Dr O’Neill and colleague Professor Chris Rayner from the University’s School of Chemistry have published their findings in the journal Scientific Reports, and believe the compound is worth serious consideration as the basis for a new drug to combat certain types of bacterial infections.
Dr O’Neill added: “y-ACT exhibits potent antibacterial activity against two important representatives of the ESKAPE* class of pathogens, which are bacteria that have developed the ability to ‘escape’ the action of existing drugs.
"A major challenge in tackling the problem of antibiotic resistance is to discover new drugs – our study shows that potentially useful drug candidates can be ‘discovered’ from amongst the antibiotics we already know about.
“The weak activity previously published for the ACT family as a whole probably explains why this group was not further evaluated, and it is intriguing to think that other potentially useful antibiotic groups are languishing in obscurity in academic journals just needing expert review using modern processes and equipment.”
Supporting Dr O’Neill’s work, Dr Jonathan Pearce, Head of Infections and Immunity at the Medical Research Council, said: “There is an urgent need to discover new ways to fight AMR and the scientific community is leaving no stone unturned in its search for new antibiotics. This includes revisiting chemical compounds that were once shelved.
“Until recently, no new antibiotics had been discovered for 25 years. Dr O’Neill’s research is important: it’s providing another way of looking for potential antibiotics and could hold the key to uncovering options that were overlooked before but may be incredibly useful now.”
At the time, scientists did not understand how it was able to stop the growth, but Dr Webb and his team have proved it is driven by Vitamin B5, which is used to metabolise energy. Bacteria have to make B5 and a key part of the machinery they use to do so is called the PanDZ complex.
Dr Webb said: “The results of our latest studyopen up the possibility of designing new drugs that use the same means to attack E. coli, but in a more effective way.”
Dr O’Neill concludes: “Our findings underscore the importance of revisiting unexploited antibiotics as a potential source of new antibiotic drug candidates. We now believe a comprehensive re-evaluation of such compounds is worthwhile, potentially offering new ways to protect against infections.”
Top picture shows a lab culture of y-actinorhodin.
Dr O’Neill’s study, Revisiting unexploited antibiotics in search of new antibacterial drug candidates: the case of y-actinorhodin, is published in the journal Scientific Reports. It was funded by the Medical Research Council, and members of the research team were supported by the Saudi Arabian Government, King Abdulaziz University and the Engineering and Physical Sciences Research Council.
Dr Webb’s study, Mechanism of regulation of pantothenate biosynthesis by the PanD-PanZ.AcCoA complex reveals an additional mode of action for the antimetabolite N-pentyl pantothenamide (N5-Pan) is published in Biochemistry. It was funded by Wellcome, and team members were supported by the University of Leeds, University of Hamburg and The German Federal Excellence Cluster.
Ioannis Delis, Physiological Society (Jul 2018), £10,000
Scott Bowen, Physiological Society (Jul 2018), £10,000
Steve Clapcote, Jamie Johnston, The Dunhill Medical Trust (Jun 2018), £254,874
Adrian Goldman, MRC (Jun 2018), £98,627
Darren Tomlinson, Michelle Peckham, Megan Wright, BBSRC (Jun 2018), £150,443
Simon Walker, Royal Society (Jun 2018), £337,601
Tom Thirkell, N8 Agrifood (Jun 2018), £14,870
Stephen Muench with Glaxo SmithKline & UCB Celltech, BBSRC Industrial Partnership Award (Apr 2018), £480,225
Steve Clapcote, BBSRC (Apr 2018), £443,072
Helen Miller, Innovate UK (Apr 2018), £999,960
Elisabetta Groppelli, David Rowlands & Stanley Lemon (University of North Carolina), Medical Research Foundation Fellowship (Apr 2018), £293,494
Nikesh Patel, Medical Research Foundation fellowship (Apr 2018), £290,976
Graham Askew with colleagues in Hull and Liverpool, BBSRC (Apr 2018), £150,498
Andrew Macdonald, Neil Ranson & Richard Foster, Kidney Research UK (Apr 2018), £82,821
Jessica Kwok & Ralf Richter, Leverhulme Trust (Apr 2018), £298,273
Julie Aspden, Royal Society (Apr 2018), £20,000
Liz Duncan, Royal Society (Mar 2018), £14,602
Alex O'Neill & Ryan Seipke, BBSRC (Feb 2018), £45,489
Jim Deuchars, Royal Society (Feb 2018), £16,300
Stefan Kepinski & Netta Cohen, Leverhulme Trust (Feb 2018), £320,387
Lisa Collins, BBSRC (Feb 2018), £49,950
Alison Baker, BBSRC (Feb 2018), £30,000
Nikita Gamper, BBSRC (Feb 2018), £30,000
Lars Jeuken, BBSRC (Feb 2018), £30,000
Scott Bowen, Leducq Foundation Grant (Feb 2018), £28,470
Jessica Kwok and Ronaldo Ichiyama, International Spinal Research Trust (Feb 2018), £94,450
Alex O'Neill, Oxford Drug Design (Jan 2018), £86,098
Dave Lewis and Colleagues in South Africa, HEFCE Global Challenge Research (Jan 2018), £48,000
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Christine Foyer and Alison Baker, HEFCE GCRF Grant (Jan 2018), £71,158
Alison Baker, Yun Yung Gong and Lindsay Stringer and ICRISAT India, HEFCE GCRF Grant (Jan 2018), £27,000
Graham Askew, Simon Walker, BBSRC (Jan 2018), £699,781
Jennifer Tomlinson, Royal Society (Jan 2018), £512,801
Alison Dunn, NERC (Dec 2017), £18,000
Jennifer Tomlinson, Royal Society-Research Fellows Enhancement Award (Dec 2017), £94,681
Helen Miller, AB AGri Grant (Dec 2017), £73,600
Simon Walker, Royal Society Enhancement Award (Dec 2017), £10,000
Carrie Ferguson, Bryan Taylor, Harry Rossiter, The Physiological Society (Dec 2017), £7,392
Ralf Richter, Royal Society (Dec 2017), £6,000
Christine Foyer, British Council Newton Fund (Dec 2017), £49,840
Adrian Whitehouse and colleagues in School of Chemistry and University of Liverpool, MRC (Nov 2017), £622,319
Michelle Peckham, Neil Ransom, MRC (Nov 2017), £495,159
Dave Lewis, British Council India (Nov 2017), £22,540
Elton Zeqiraj, Royal Society (Nov 2017), £15,000
Hannah Dugdale, Royal Society (Nov 2017), £15,000
Shaunna Burke, Cancer Research UK Innovation Grant (Nov 2017), £20,000
Alex O'Neill and colleagues in Chemistry, BBSRC (Nov 2017), £431,865
Jessica Kwok, Wings for Life (Nov 2017), £87,365
Tom Bennett, BBSRC (Oct 2017), £523,679
Neil Ranson, Darren Tomlinson, BBSRC (Oct 2017), £494,318
Nikita Gamper, BBSRC (Oct 2017), £490,426
Amanda Bretman and colleagues from UEA, NERC (Oct 2017), £430,886
Juan Fontana, Rosetrees Trust consumables grant (Oct 2017), £22,500
Helen Miller, DSM Nutritional Products AG (Sep 2017), £69,988
Neil Ranson, Juan Fontana, Mark Harris, Michelle Peckham, Ralf Richter, Peter Stockley, Patricija Van Oosten-Hawle and colleagues in Engineering, FMH and MAPS, Wellcome Trust Equipment Call (Sep 2017), £418,000
Jamie Johnston, Physiological Society (Sep 2017), £10,000
Frank Sobott, Adrian Goldman, Mark Harris, Andrew Macdonald, Stephen Muench, Sheena Radford and colleagues in FMH and MAPS, Wellcome Trust Equipment Call (Aug 2017), £415,000