Breast Milk Protein Is Danish Prince, Antibacterial Adjuvant
By Anette Breindl
Scientists have found that a protein complex present in breast milk can act as an adjuvant for a range of antibiotics, sensitizing Staphylococcus aureus bacteria to antibiotics to which they have become resistant.
The protein complex, HAMLET, has a multifaceted history as far as drug discovery is concerned. It was originally identified, Anders Hakansson told BioWorld Today, as part of a project looking at how breast milk protects babies from infections. But Hakansson and his colleagues soon discovered that it killed cancer cells HAMLET stands for Human Alpha-lactalbumin Made Lethal to Tumor Cells, which it enters and kills by disrupting mitochondrial function.
Hakansson ultimately returned to studying the complex' antibacterial effects, however. Last year, he and his colleagues showed that HAMLET "has antibacterial effects on its own, and kills primarily upper respiratory tract infections," such as Streptococcus pneumoniae.
In that paper, Hakansson said, he and his colleagues used Staphylococcus aureus as a negative control because earlier screening had shown that HAMLET did not kill it. But in doing so, they noticed that "we do have an effect on the same pump" that is responsible for the demise of S. pneumonia when they are exposed to the drug.
HAMLET works by binding to a hydrogen pump in the bacterial membrane, preventing that pump from getting rid of hydrogen atoms. The resulting changes in pH value ultimately leads to an influx of calcium into the bacteria, which kills them by a process resembling apoptosis.
Because of that effect, Hakansson and co-authors Laura Marks and Emily Clementi all of whom are at SUNY Buffalo hypothesized that if they gave HAMLET in combination with other drugs, the combination might push bacteria over the edge.
In their experiments, which were published in the May 1, 2013, edition of PLoS ONE, the team conducted tests in both cell culture and in animals to see specifically whether treating drug-resistant Staphylococcus strains with HAMLET and an antibiotic could restore sensitivity to the latter. Drug-resistant S. aureus strains such as MRSA are becoming an increasing public health headache as they spread from hospitals into the community, and can in some cases kill previously healthy individuals.
The researchers found that they were indeed able to do so for a variety of antibiotics, including methicillin and, in some but not all strains, vancomycin, the current antibiotic of last resort to which resistance is now emerging. "We were able to get them all back into the sensitive range," Hakansson said.
One encouraging finding is that when Hakansson and his team repeatedly exposed bacteria to increasing concentrations of HAMLET which is the classical way to breed drug resistance in bacteria such resistance did not emerge.
Developing resistance, of course, is one of the things bacteria do best, and Hakansson acknowledged that "you never know" what will happen once any antibacterial agent makes it into widespread clinical use.
But he did note that "the situation looks pretty good... we tried really hard to breed resistance in the lab and couldn't do it."
He said he believes one reason is that bacteria may be good at evolving resistance, but mothers are just as good at protecting their babies, for exactly the same evolutionary reasons. HAMLET is "a natural molecule that has evolved over millions of years," Hakansson pointed out. "It is a target that the bacteria cannot easily inactivate."
And the pump that HAMLET binds to, he added, appears to be so optimized that "it is difficult to change. . . . Bacteria with a changed pump don't grow well."
Hakansson said that if the work pans out, HAMLET could ultimately be a broad-spectrum adjuvant. The molecule has shown activity against the pump of multiple bacterial species, including E. coli and enterococci, although with the exception of a few respiratory pathogens, it is not able to kill them on its own. Currently, there is no such adjuvant on the market, although a few other labs and companies are looking into ways to boost the effectiveness of existing antibiotics. (See BioWorld Today, Jan. 17, 2013, and Sept. 11, 2009.)
With his wife Hazeline, Hakansson is a co-founder of a start-up, Evincor LLC, which was founded last year to develop HAMLET further.
An adjuvant, he pointed out, should make more economic sense to develop than antibiotics that specifically target drug-resistant bacteria and as antibiotic resistance grows, that market will, too.