Vaccine Candidate Makes Bacterium Vulnerable, Antibiotics Kill More

One-two punch has potential to treat chronic, recurrent ear and other infections with lower antibiotic doses

Researchers in the Center for Microbial Pathogenesis have found a possible new approach to treating chronic, recurrent middle ear infections by combining a vaccine candidate they developed with low doses of traditional antibiotics.

The vaccine candidate targets nontypeable Haemophilus influenzae (NTHI), the most dominant bacteria species causing the infections. But NTHI is often found with other species of bacteria in infections.

In this benchtop research, the investigators show that antibodies created by the vaccine candidate disrupt the biofilm that protects NTHI and the bacteria Moraxella catarrhalis (Mcat). The pair are one of the most common teams causing middle ear infections in children.

As antibodies disrupt the biofilm, both bacteria disperse. Importantly, “in this process, the bacteria become highly sensitive to antibiotic killing,” says Elaine Mokrzan, PhD, chief research associate and leader of the study.

Mokrzan and Lauren Bakaletz, PhD, director of the center, showed that antibiotics, including amoxicillin or clarithromycin, killed a significant percentage of the bacteria dispersed from the biofilm, at dosages that killed fewer bacteria floating free in a solution and none in an intact biofilm.

The research is published in mBio.

“There’s a big problem with antibiotic resistance, especially in chronic infections and diseases,” Dr. Bakaletz says. “This two-pronged approach was called ‘our best shot at combatting drug-resistant microbes,’ by one of the leaders in the field several years ago.”

In this case, the vaccine candidate targets one microbe, but because the two microbes become intimately related, the vaccine disrupted both of them. Dr. Bakaletz says. “That’s an added but unexpected benefit.”

Using a scanning electron microscope and tagging the bacteria with different fluorescent colors, Mokrzan and Bakaletz made some surprising findings.

They expected NTHI and Mcat would be distributed in the biofilm like salt and pepper sprinkled on a plate. They saw that Mcat formed towers and NTHI grew around, up and over them.

Mcat alone, protected in its own biofilm, did not disperse from its biofilm when exposed to the vaccine-candidate-induced antibodies. 

But, when the biofilm containing both species was exposed to antibodies, the researchers detected initial signaling by NTHI but not by Mcat. Looking closer, they found that Mcat appears to “eaves drop” on a second set of signals by NTHI, and both disperse, the investigators say.

Dr. Mokrzan is now leading the effort to learn why the microbes are more sensitive to antibiotics when they disperse from the biofilm and for how long, in order to maximize the treatment strategy.

“We hope this strategy can stop the cycle of repeated infections,” she says.

The strategy is likely applicable to sinus and other ear infections, respiratory infections in people with cystic fibrosis, catheter and central line infections, livestock infections and more, Dr. Bakaletz says.  

Citation: Mokrzan EM, Novotny LA, Brockman KL, Bakaletz LO. Antibodies against the majority subunit (PilA) of the type IV pilus of nontypeable Haemophilus influenza disperse Moraxella catarrhalis from a dual-species biofilm. MBio. 2018 Dec 11;9(6). pii: e02423-18.