Scientists have discovered a highly effective method to produce novel aminocoumarins, antibiotics that are useful in the fight against drug-resistant bacteria that could represent a new antibacterial class to tackle the growing problem of antibiotic resistance.
The development of bacterial resistance to antibiotics is now a major public health concern, even more so as hospital infections such as vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) are now beginning to spread into the general community, at a time when pharmaceutical companies are reining back their spending on new anti-infectives.
Currently, doctors have few weapons to fight these strains. Though some of these "super bugs" are sensitive to aminocoumarins. Caren Meyers, senior researcher at Harvard Medical School told DrugResearcher.com: "Using this method, we hope to be able to overcome some of the problems such as low solubility, instability in serum and poor pharmacokinetics of aminocoumarins. We also will continue to learn about the structure activity relationships between coumermycin A1 and its target DNA gyrase. Manipulating the structure enzymatically will help us toward this goal.
The method developed by the researchers exploits bacterial enzymes and uses an alphabet soup of proteins from Streptomyces to make an enzymatic production line that adds, different chemical moieties to the backbone of coumermycin A1, a member of the aminocoumarin family of antibiotics.
Starting with this coumermycin scaffold, researchers used an enzyme CouL to add one or two amino groups, then CouM was used to add a sugar component called L-noviose. The enzyme CouP was found to add methyl groups to the CouM products, and NovN was used to add one or two carbamoyl moieties to methylated CouP product variants.
By playing mix-and-match with enzymes and CouL substrates that make up the coumermycin A1 backbone, multiple designs can be rolled off the production line. In total a library of nine coumermycin variants were generated.
It is thought the sugar moieties attached to the coumermycin backbone are thought to bind to and inactivate the essential bacterial topoisomerase DNA gyrase. Indeed, three of these compounds have been produced in sufficient quantity for detailed analysis, and they are currently undergoing biological evaluation.
Meyers said: "Producing the aminocoumarins might be made economically viable following optimisation of each enzymatic step. Currently, synthetic methods for introducing sugar moieties are difficult and cumbersome. The enzymatic route is highly efficient allows aminocoumarin manipulation, generating libraries of aminocoumarin analogs."
Meyers added that while they've not had any interest from industry yet the method for generating aminocoumarins was still at the "proof of principle" stage.
The emergence of resistant bacterial strains has renewed interest in the aminocoumarin novobiocin, which is one of the few drugs available that is effective against MRSA. Indeed, the annual cost for treating antibiotic resistant infections is approximately $30 billion (€25.7bn) in the USA alone.
"The challenge of producing antibiotics to kill drug resistant bacteria will continue because bacteria will continue to find ways of becoming resistant to drugs. It is an ongoing problem and will continue to pose a challenge in drug development," Meyers added.