Common tuberculosis therapy D-cycloserine has shown to have second chemical action when combating bacteria enzymes.
David Roper, PhD, MRC, BSc
Molecular analysis of a second-line antibiotic therapy has given researchers indications for future improved treatments for bacterial infections.
Researchers from the UK-based University of Warwick and The Francis Crick Institute have uncovered varying chemical actions of D-cycloserine, a longtime antibiotic drug with proven efficacy — but a burden of adverse effects — in treating microbial conditions such as tuberculosis (TB).
The drug is designed to inhibit the D-alanine racemase (Alr) and D-alanine—D-alanine ligase (Ddl) enzymes, which are required to build and maintain bacterial cell walls.
While D-cycloserine inhibits the Alr enzyme by forming a molecular bond with a chemical group, the researchers found that the antibiotic undergoes chemical modification to inhibit the Ddl enzyme. Its modification is a chemical species never before documented.
By the researcher’s count, it may be the only antibiotic in the world known to act in different chemical manners to attack different bacterial targets. Ironically, the chemical makeup of D-cycloserine is very simple, lead author David Roper, PhD, MRC, BSc, professor of Biochemistry and Structural Biology in the School of Life Sciences at the University of Warwick, told MD Magazine.
The antibiotic is produced by certain soil bacteria in the first place that can still be used as second-line TB treatment.
“Once of the reasons it is not used more widely concerns the psychotic side effects of D-cylcoserine treatment,” Roper said. “Now we know what happens to the drug when it works as an antibiotic there may be a way to subtly alter its chemical structure to retain the antibiotic effects but avoid the psychotic side effects.”
The uncovered analysis lends credence to the broad idea that more antibiotics should be assessed beyond their initial indications. Roper noted that penicillin drugs work in a larger complexity than originally intending.
“Certainly we should understand at a higher level how antibiotics work to tease out the biology and chemistry that may lead to new drugs, but also to understand how resistance to these drugs might arise so that we can avoid this or at least make it less likely,” Roper said.
Particularly in respect to TB, the need for advanced therapies to combat drug-resistant bacteria is greatly needed. Antibiotic administration is complicated due to a lack of diagnostics ensuring the right drug is being provided, to a history of patient non-compliance with the drugs themselves, Roper said.
Such issues can be amplified in areas with less clinical resources.
“The biology of TB infection is complex and requires long term treatment with antibiotics, often in the poorest countries of the world where the supply of drugs for such long-term treatment is a long way from being assured,” Roper said.
Luiz Pedro Carvalho, PhD, MSc, from the Mycobacterial Metabolism and Antibiotic Research Laboratory at the Francis Crick Institute, said the study has uncovered the fact that researchers know far less about antibiotic function and bacteria resistance than previously realized.
“Only by truly understanding molecular and cellular events caused by antibiotics or in response to their presence will we truly understand how to make improved drugs, which are much needed in face of the current threat of antibiotic resistance,” Carvalho said.
Moving forward, researchers hope to modify D-cycloserine’s structure to resemble the discovered chemical species, and to then produce it as an antibiotic void of some of the original therapy’s adverse effects. Roper expressed hope to MD Magazine in finding a partner capable of the task.
The study, "Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine," was published online in Nature Communications this week.
A press release regarding the study was made available.