Scientists have taken a significant step toward the design of a new class of antibiotics for fighting drug-resistant bacterial infections like tuberculosis. In a study published in Nature Chemical Biology, they describe some new compounds that attack a previously untargeted enzyme that is essential for building and maintaining the cell walls of bacteria.
The team suggests the findings could also lead to cheaper, more accessible treatments for tuberculosis (TB).
Corresponding author Gyanu Lamichhane, associate professor of medicine at the Johns Hopkins University School of Medicine in Baltimore, MD, says:
"The complexity of TB treatment and growing prevalence of antibiotic resistance is a serious threat to public health."
TB - a disease caused by bacteria that spread through the air - still kills more people worldwide than any other infection, say the Centers for Disease Control and Prevention (CDC).
For decades after, scientists and doctors managed the problem of antibiotic resistance by developing new drugs. However, in the 1980s, there was a decline in research and development of antibiotics as focus shifted to other drugs.
Fewer drugs entering in the pipeline, coupled with the liberal and sometimes mismanagement of antibiotic use, has given the bacteria the opportunity to catch up with - and in some cases outpace - our ability to kill them.
For example, multidrug-resistant (MDR) TB is a major health threat globally. Estimates suggest nearly half a million MDR-TB cases occur worldwide annually, including cases of extensively drug-resistant TB (XDR-TB).
While still relatively rare in the United States, MDR-TB and XDR-TB are very expensive to treat. Also, treatment takes a long time, disrupts lives, and has potentially life-threatening side effects.
New carbapenems cured TB in mice
Prof. Lamichhane says one reason for the new research is the fact that over half of antibiotics given to patients today belong to a class known as beta-lactams.
- The use of antibiotics is the single most important factor giving rise to antibiotic resistance globally
- In the U.S., over 2 million people become infected with antibiotic-resistant bacteria every year
- At least 23,000 Americans die each year from antibiotic-resistant infections.
These drugs work by disrupting an enzyme called DD-transpeptidase that is important for building and maintaining the walls of the bacterial cell. Without the enzyme, the bacteria quickly die.
However, about 10 years ago, researchers found another enzyme called LD-transpeptidase - that is also important for cell wall production - allows bacteria like TB to survive antibiotics.
In the new study - with the help of a sophisticated imaging system called protein X-ray crystallography - the team investigate the detailed molecular structure of LD-transpeptidase extracted from many species of bacteria.
Armed with knowledge about the new enzyme's structure, the researchers then experimented with molecules that might work against it. They tested new compounds from a subclass of the beta-lactam antibiotics that bind specifically to the new enzyme.
Using live bacterial cultures, they showed that the compounds - called carbapenems - block the wall-building enzyme. They showed this also worked in a group of bacteria that the CDC call ESKAPE pathogens and see as a particular threat because of their ability to develop drug resistance.
The team also tested two of the carbapenem compounds in different groups of TB-infected mice. They found that even without use of classic TB antibiotics, the new compounds - and biapenem in particular - cured the mice of TB.
"Our data show that the carbapenems successfully treated TB infections alone by attacking the right enzyme."
Prof. Gyanu Lamichhane
The team is now planning to start clinical trials to test the safety and efficacy of some of these new compounds.