Bacterial resistance to antibiotics is a growing global problem, and contamination of soil and waterways by antibiotics is exacerbating the issue as resistance genes are readily transferred between bacterial communities. Some soil organisms aren’t just resistant to antibiotics, they can help to break them down or even use antibiotic drugs as a food source. What scientists haven’t understood is how bacteria use drugs such as penicillin as a source of carbon for energy.

A team led by scientists at Washington University in St Louis School of Medicine has now identified the genes and biochemical pathways that underpin the mechanisms employed by some bacteria to catabolize the antibiotic penicillin. Senior researcher Gautam Dantas, Ph.D., and colleagues then used their findings to help engineer a harmless strain of Escherichia coli that can use penicillin and its degradation product as a sole carbon source. Describing their studies in a paper in Nature Chemical Biology, they claim that it may be possible to use bacterial strains as tools for cleaning up environments that are contaminated by antibiotics, which can represent important drivers of antibiotic resistance development. Identifying bacterial pathways involved in the catabolism of antibiotics could also help scientists to develop enzymes for generating new antibacterial drug candidates.

“With some smart engineering, we may be able to modify bacteria to break down antibiotics in the environment,” comments Terence Crofts, Ph.D., who is lead author of the team’s paper, which is entitled, “Shared Strategies for β-Lactam Catabolism in the Soil Microbiome.”

Modern industrial and agricultural practices lead to environmental contamination by antibiotics. In some countries, pharmaceutical companies that manufacture huge quantities of antibiotics for global use discharge antibiotic-laden waste into local waterways. In other countries, including the U.S., farmers may routinely add antibiotics to their animal feed, which generates antibiotic-loaded animal waste ending up in the soil or waterways. Such contamination plays a key role in the rise of antibiotic resistance, the authors suggest.

Most antibiotics are either natural products, or are derived from natural products, and were originally isolated from soil bacteria, they continue. Antibiotics also contain carbon, so its not unreasonable to assume that some bacteria have evolved to use these soil compounds as a source of fuel. “Given their soil origin, and the lack of environmental accumulation of these organic compounds, it is natural that some antibiotics are consumed by soil bacteria as carbon or nitrogen sources,” the researchers point out.  “Antibiotic resistance enzymes are known to be plentiful in soil habitats, and it is only because of their medical exploitation that antibiotics are treated as privileged molecules not bound by the carbon cycle.”

“Ten years ago we stumbled onto the fact that bacteria can eat antibiotics, and everyone was shocked by it,” comments senior author Dantas, who is associate professor of pathology and immunology, of molecular microbiology, and of biomedical engineering.  “But now it's beginning to make sense. It's just carbon, and wherever there's carbon, somebody will figure out how to eat it.”

In fact, studies have demonstrated that different bacteria, including commonly studied Pseudomonas strains, can utilize various antibiotics, including the β-lactam (penicillin) antibiotics, as a source of carbon. However, as the researchers write, not only is evidence conflicting as to which part of the penicillin molecule is used as a carbon source, but “little is known about the pathways and enzymes used during catabolism, including whether ß-lactamase activity is required.…To date, no specific genes or pathways have been identified that enable bacteria to use antibiotics as a sole carbon source.”

To try and provide answers to these questions, the Washington University School of Medicine researchers studied four very distantly related species of soil bacteria that can grow on a diet of penicillin alone. They found that the bacteria all switched on three specific sets of genes when given penicillin as a food source, but not when sugar was provided as an alternative. These genes controlled the three stages in penicillin catabolism by the bacteria, the first of which is deactivation of the toxic portion of the antibiotic molecule.

First, β-lactamase is preferentially upregulated in response to penicillin. This is followed by expression of a putative penicillin utilization operon (put). And finally, the pathway appears to be completed by upregulation of the phenylacetic acid catabolon (paa). “This architecture suggests a catabolic pathway consisting of the following steps,” the researchers write. ”…(i) detoxification of penicillin via hydrolysis of the β-lactam ring by a β-lactamase, a canonical β-lactam antibiotic resistance enzyme, (ii) import of the benzylpenicilloic acid product and/or hydrolysis of the amide bond to free the carbon-rich phenylacetic acid side chain, and (iii) processing of phenylacetic acid into acetyl-CoA [acetyl-coenzyme A] and succinyl-CoA via the phenylacetic acid catabolon.”

The team then used their discoveries to engineer an E. coli strain that could use penicillin as its only source of carbon. “With limited further engineering, these strains could be developed as tools for in situ bioremediation of antibiotic-contaminated soils or environments, such as those located near pharmaceutical manufacturers,” the authors state. Or, as Dr. Dantas puts it, “Now that we understand how these bacteria do it, we can start thinking of ways to use this ability to get rid of antibiotics where they are causing harm.…You couldn't just douse a field with these soil bacteria today and expect them to clean everything up,” Dantas said. “But now we know how they do it. It is much easier to improve on something that you already have than to try to design a system from scratch.”

The researchers claim the pathway identified “uniquely provides a mechanistic connection between antibiotic producers, antibiotic resistance, and antibiotic catabolism.” Antibiotic-catabolizing enzymes also have the potential to play what they suggest is “an important industrial role in the production of next-generation antibiotics in the same way that the discovery of penicillin amidase spurred the development of semisynthetic β-lactams through remodeling of natural penicillins.…Antibiotic degradation may therefore paradoxically contribute to the development of the next generation of novel antibiotics.”


 








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