How Some Antibiotics Defeat Drug-Resistant Bacteria: It’s the “Push” That Counts

Current antibiotics may be modified to overcome resistance, authors say

Antibiotics can kill drug-resistant bacteria if they “push” hard enough into bacterial cells, according to a study from University College of London. The study, published in Scientific Reports, opens up a promising new way of overcoming antibiotic resistance and could help scientists design more-effective drugs, according to the authors.

“Antibiotics work in different ways, but they all need to bind to bacterial cells in order to kill them,” lead author Dr. Joseph Ndieyira explained. “Antibiotics have ‘keys’ that fit ‘locks’ on bacterial cell surfaces, allowing them to latch on. When a bacterium becomes resistant to a drug, it effectively changes the locks so the key won’t fit any more. We found that certain antibiotics can still ‘force’ the lock, allowing them to bind to and kill resistant bacteria because they are able to push hard enough. In fact, some of them were so strong they tore the door off its hinges, killing the bacteria instantly.”

The researchers used sensitive equipment to measure the mechanical forces that four different antibiotics exerted on bacterial cells. They tested bacteria that were susceptible to antibiotics and those that had developed resistance. The antibiotics all exerted similar forces on susceptible bacteria, but the forces they exerted on resistant bacteria varied significantly. The antibiotics tested included vancomycin, a powerful antibiotic used as a last-resort treatment for patients with methicillin-resistant Staphylococcus aureus (MRSA) and other infections, and oritavancin, a modified version of vancomycin used against complex skin infections.

“We found that oritavancin pressed into resistant bacteria with a force 11,000 times stronger than vancomycin,” Ndieyira said. “Even though it has the same ‘key’ as vancomycin, oritavancin was still highly effective at killing resistant bacteria. Until now, it wasn’t clear how oritavancin killed bacteria, but our study suggests that the forces it generates can actually tear holes in the bacteria and rip them apart.”

Oritavancin is a fast-acting antibiotic that can kill bacteria in 15 minutes, whereas vancomycin takes six to 24 hours. Vancomycin works by disrupting vital processes in bacteria so that they slowly stop functioning and die. Although oritavancin is a modified version of vancomycin, the new study suggests that it kills bacteria in a completely different way.

“Oritavancin molecules are good at sticking together to form clusters, which fundamentally changes how they kill bacteria,” Ndieyira said. “When two clusters dig into a bacterial surface, they push apart from each other, tearing the surface and killing the bacteria. We found that conditions at the bacterial surface actually encourage clustering, which makes antibiotics even more effective.”

The team developed a mathematical model to describe how antibiotics behave at the surface of bacterial cells. The model, they say, could be used to identify new drugs that can kill bacteria by using brute force.

“Our findings will help us not only to design new antibiotics but also to modify existing ones to overcome resistance,” Ndieyira said. “Oritavancin is just a modified version of vancomycin, and now we know how these modifications work we can do similar things with other antibiotics. This will help us to create a new generation of antibiotics to tackle multidrug-resistant bacterial infections, now recognized as one of the greatest global threats in modern health care.”

Sources: Medical Xpress; February 3, 2017; and Scientific Reports; February 3, 2017.