SMU chemistry professor and team refine and test new tuberculosis treatments

Tuberculosis is the world’s most deadly infectious disease, killing approximately 1.3 million people worldwide each year. The combinations of powerful antibiotics used to treat the most drug-resistant cases can prove so hard to tolerate that some patients simply stop taking them, speeding death from the disease.     

But an SMU-led team funded by the National Institutes of Health (NIH) has found a new way to destroy multidrug-resistant strains of Mycobacterium tuberculosis. The team’s research is creating hope for an oral medication that can fight the toughest cases with fewer side effects.      

For more than ten years, SMU chemistry professor John Buynak has been structurally altering antibiotics, leading to a modified version of a class of antibiotics that weaken the cell wall of mycobacterial strains, causing bacteria to burst and die.   

What makes it so hard to destroy is that the bacteria causing tuberculosis has “figured out” how to block most antibiotics from dismantling the bacterial cell wall.   

Initial lab testing is promising – shown to be 20-times more effective at killing mycobacterial strains than traditional antibiotics known as carbapenems. And unlike existing carbapenems, Buynak’s modified version may be less likely to negatively affect normal bacteria and cause unnecessary side effects such as vomiting, itchy skin or fevers. 

Now, with a $3.5 million NIH grant, Buynak and scientists from the University of Central Florida, the U.S. Naval Academy and the University of Kentucky are collaborating to see if there might be an even better version of the atypical carbapenem that Buynak created. They are also seeing if they can turn this atypical carbapenem into a drug that can be taken orally by patients.  

“If properly developed, these new antibiotics will provide clinicians with a fallback strategy in treatment of patients infected with highly resistant mycobacterial strains,” Buynak said.   

Current treatment for multidrug-resistant tuberculosis involves giving patients combinations of powerful antibiotics over a course of months and it is often poorly tolerated by the patient, leading to a high mortality rate.    

Drugs called beta-lactam antibiotics, including carbapenems, had been written off as a possible way to treat particularly resistant mycobacterial strains, because mycobacteria’s defense mechanism had made them ineffective.   

But Buynak’s new atypical carbapenem has an entirely different way to kill the cell wall.   

“A different target means that we can use a different ‘magic bullet’ to target them,” Buynak said, explaining that selectively inhibiting a specific enzyme allows beneficial bacterial strains to survive the antibiotic while selectively killing the mycobacterial strains.   

The extremely tough task of modifying an existing antibiotic required Buynak’s extensive knowledge of what different elements – like carbon or oxygen – would and wouldn’t do in a chemical reaction, so he could use a series of simpler chemical reactions to construct increasingly complex molecular architectures.    

“We were the first to make this particular new class of beta-lactams and thus we needed to develop a new synthetic strategy to generate them,” the molecular chemist said. “It took about two years of trial and error before we succeeded.”  

Buynak’s work has benefits beyond discovery: education. Buynak has put SMU students to work in creating this new disease-fighting antibiotic: Four graduate students and more than 20 undergraduates. 

It also took several more years to determine that the atypical carbapenem was particularly good against Mycobacterium tuberculosis, relative to other strains. Atypical carbapenem was also found to be an effective way to kill other mycobacterial strains, like that which causes leprosy.  

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