A way to make bacteria more vulnerable to a class of antibiotics known as quinolones, which include ciprofloxacin and are often used to treat infections such as Escherichia coli and Staphylococcus aureus, MIT researchers.
The new strategy is that they often fail against infections that feature a very high density of bacteria, which help them to overcome a key limitation of these drugs. These include many chronic, difficult-to-treat infections, such as Pseudomonas aeruginosa, often found in the lungs of cystic fibrosis patients, and methicillin-resistant Staphylococcus aureus (MRSA).
James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science (IMES) and Department of Biological Engineering and the senior author of the study, says, “Given that the number of new antibiotics being developed is diminishing, we face challenges in treating these infections. So efforts such as this could enable us to expand the efficacy of existing antibiotics.”
Overcoming bacterial defences
Bacteria that have become tolerant to a drug enter a physiological state that allows them to evade the drug’s action. (This is different from bacterial resistance, which occurs when microbes acquire genetic mutations that protect them from antibiotics.)
Collins says, “Tolerance is not well-understood, and we don’t have the means to circumvent it or overcome it.”
Collins and his colleagues found that they could increase the ability of antibiotics known as aminoglycosides to kill drug-tolerant bacteria by delivering a type of sugar along with the drug, from a study published in 2011.The sugar helps to boost the metabolism of the bacteria, making it more likely that the microbes will undergo cell death in response to the DNA damage caused by the antibiotic.
Deliberating serious side effects of aminoglycosides, they are not widely used. In their new study, Collins and his colleagues decided to explore whether they could use a similar approach to boost the effectiveness of quinolones, a class of antibiotics used more often than aminoglycosides. Quinolones work by interfering with bacterial enzymes called topoisomerases, which help with DNA replication and repair.
The researchers found that it wasn’t enough to add just sugar with quinolones so they also had to add a type of molecule known as a terminal electron acceptor, which plays an essential role in cellular respiration, the process that bacteria use to extract energy from sugar.
In cells, the electron acceptor is usually oxygen, but other molecules, including fumarate, an acidic organic compound that is used as a food additive, can also be used.
Collins says, “If you simply add a carbon source like glucose, that’s not enough to enable the quinolone to kill. If you simply add oxygen, or another terminal electron acceptor, that by itself is not enough to cause killing either. But if you combine the two, you can eradicate the tolerant infection.”
Metabolic state
The findings suggest that high-density bacterial infections rapidly consume nutrients and oxygen from their environment, which then provokes them to enter a starvation state that helps them to survive. In this state, they greatly reduce their metabolic activity, which allows them to avoid the cell death pathway that is normally triggered when DNA is damaged by antibiotics.
Collins says, “This finding highlights that the metabolic state of the bug significantly influences how the antibiotic will impact the bug. And, for the antibiotic to be effective as a killing agent, it requires downstream cellular respiration as part of the process.”
Karl Drlica, a professor at the Public Health Research Institute at Rutgers New Jersey Medical School, who was not involved in the research, “This study encourages work to find new ways to stimulate bacterial respiration and thereby enhance the production of reactive oxygen (or even non-oxygen) species during antibiotic treatment, for better eradication of bacterial pathogens, particularly those having low metabolic activity that may render them tolerant to antimicrobials.”