Reassessing Discarded Chemicals in Search of New Antibiotics
The growing prevalence of antibiotic resistance in pathogenic bacteria is severely eroding our ability to manage bacterial infection. Central to an effective response to this problem will be the development of novel antibacterial drugs that display activity against bacteria resistant to existing antibiotics.
In one of such quests, University of Leeds scientists are taking time out to revisit long-forgotten, discarded chemical compounds to find if any of them possess any requisite properties of an antibacterial drug.
By initiating the discovery process with compounds about which something is already known, including the fact that they possess antibacterial activity, this approach offers a potential fast-track through the challenging early stages of discovery, write the scientists.
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.
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A family of compounds, known as the actinorhodins, was originally identified in the 1940s and was pronounced as having weak antibiotic properties, thereby not taken forward for development into a drug.
But Dr O’Neill now claims that this chemical was not fully appreciated at the time attributable to how scientists at the time 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 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.”
Another research in the university was led by Dr Michael Webb, whose research focuses on a compound, called pentyl pantothenamide.
First introduced in the 1970s, it was found to be able to stop the growth of E.coli but not completely kill the bacteria, therefore was deemed useless and was never taken into clinical use. Scientists who first analysed the compound 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. Pentyl pantothenamide targets the PanDZ complex, preventing E. coli from making Vitamin B5 and so starving it of the means to grow.
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.”
Each year, the Medical Research Council spends approximately £6.5 million on AMR-related research. With decades of work, MRC researchers have pioneered innovations in AMR research from mapping how infections spread, discovering new resistance mechanisms, and identifying new antibacterial compounds.
The next frontier is to usher in a new class of antibiotics to tame superbugs that have steadily built resistance to our current arsenal of therapies, including last-resort options to fight multi-drug resistant bacteria.