Breakthroughs Blog: Antimicrobial resistance

Penicillin, the world’s first antibiotic, works by targeting certain proteins—appropriately named penicillin-binding proteins (PBPs)—that play a critical role in building and maintaining the bacterial cell wall. Now, scientists at Harvard Medical School have identified another class of proteins which play a similar role and could be a target for the next generation of antibiotics. The road to discovery started in 2003, when it was determined that certain bacteria could grow without PBPs. In their absence, the proteins responsible for maintaining cell wall shape, elongation, division, and spore formation (SEDS proteins) continued to function normally, enabling the bacteria to thrive. SEDS proteins are found in more types of bacteria than PBPs, and consequently a treatment targeting SEDS proteins could have even broader application than penicillin. On February 22, the Obama Administration requested US$1.9 billion in emergency funding for the Zika response, and 181 days later, Congress has yet to approve it. Consequently, the Department of Health and Human Services (HHS) has shifted $81 million from other programs to support Zika vaccine research and development—$34 million of which will go to the National Institutes of Health (NIH) and $47 million of which will be allocated to the Biomedical Advanced Research and Development Authority (BARDA). Earlier this year, HHS repurposed $589 million in funding from the Ebola response to combat Zika, however, that funding will run out by the end of this month. The NIH will use its funding for human clinical trials of its leading Zika vaccine candidate, however, the agency will need an additional $196 million for additional trials and to advance a second and third candidate. BARDA’s funding will enable the agency to secure contracts and establish partnerships for Zika vaccine development, however, an additional $342 million will be required to continue its work. New research suggests that infection with the Plasmodium parasite, which causes malaria, could reduce the severity of Ebola infection. A team of scientists at the US National Institute of Allergy and Infectious Diseases has examined 1,868 blood samples from an Ebola treatment unit in Liberia—1,182 of which tested positive for Ebola—concluding that patients co-infected with malaria were 20 percent more likely to survive. These results held true even when controlling for the patient’s age and viral load. Viral load actually correlated with survival rates: those with the highest levels of Plasmodium had an 83 percent survival rate, compared to 46 percent of those only infected with Ebola. At the treatment center, all patients were provided with antimalarials, and consequently, treatment for malaria was not responsible for survival rates. While the reason for this trend remains a mystery, Drs. Emmie de Wit and Kyle Rosenke—the study’s lead scientists—suspect that an existing malaria infection expedites the immune response to Ebola, consequently increasing survival rates.

Reducing unnecessary antibiotic use is widely considered a priority action in combating the spread of antimicrobial resistance. In the United States, one-third of antibiotic prescriptions are unnecessary and each year, there are 27 million gratuitous prescriptions for respiratory infections alone. Rapid, point-of-care diagnostics that can discern if an infection is bacterial could significantly reduce this practice, preventing antibiotic prescriptions for viral, parasitic, or fungal infections. There are now several tests in the pipeline which evaluate the level of C-reactive protein (CRP) in the bloodstream, a molecule associated with inflammation. CRP levels increase significantly in response to bacterial infections, but only slightly in response to viral infections. Not only have several of these tests proven reliable, but new research conducted by the Oxford University Clinical Research Unit in Vietnam indicates that such a test can successfully decrease antibiotic prescriptions for respiratory infections in low-resource settings. The study monitored antibiotic use for 2,000 patients at ten primary health centers, and use of the test reduced prescriptions from 78 to 64 percent, without impacting clinical recovery or patient satisfaction rates. Scientists have identified a compound that shows promise in treating three different parasitic diseases—Chagas disease, sleeping sickness, and leishmaniasis—that effect 20 million people and result in 50,000 deaths each year. The three diseases are caused by distinct parasites and transmitted by different vectors. Chagas disease results in cardiac complications, sleeping sickness causes neurological symptoms, and leishmaniasis manifests as skin sores and liver and/or spleen damage. Existing treatments are toxic, expensive, and difficult to administer in low-resource settings. The compound—GNF6702—was developed by pharmaceutical company Novartis and discovered after screening 3 million molecules in the company’s compound library. The molecule was then modified, resulting in a drug with 20 times the original potency. The compound targets proteasome—which breaks down waste—in all three parasites, but does not have the same effect in mammal cells. The drug has proven effective in mice, and will undergo additional safety tests before the initiation of human clinical trials.  The US Agency for International Development (USAID) announced last week the initial winners of its Combating Zika and Future Threats Grand Challenge, through which the agency will be providing more than US$15 million for the development and introduction of 21 innovative tools and interventions. In just two months, USAID received and reviewed nearly 900 applications, addressing various parts of outbreak prevention, detection, and control, including vector control, personal and household protection, vector and disease surveillance, community engagement, and diagnostic innovations. The winners include an electric force field to repel mosquitoes; a flip phone–based app that can distinguish between mosquito species, enabling crowdsourced vector surveillance; insecticide-treated sandals; and a human-scented mosquito trap. The agency will announce additional winners in the next month and will invest up to $30 million total.

Researchers at the University of Pennsylvania have designed a placenta-on-a-chip: a small device that mimics the placental barrier, enabling scientists to study the transport of molecules from mother to fetus. The silicone device contains a permeable membrane surrounded by endothelial and trophoblast cells, which are found in fetal blood vessels and where the placenta meets the maternal blood supply, respectively. The model imitates the development of the placenta throughout pregnancy, as trophoblast cells merge and as the barrier becomes thinner. Previously, donated placental tissue has been used in research, however samples are scarce and only viable for a few hours after delivery. The team completed an initial, successful test of the device by comparing the transfer of glucose across the placental barrier in both donated tissue and the placenta-on-a-chip. As testing continues, plans are underway to use the device in studies on preterm birth. The secret to fighting methicillin-resistant Staphylococcus aureus (MRSA) could be an antibiotic produced by the microbes inhabiting the human nose. MRSA is a dangerous bacterium, resistant to several leading antibiotics, that causes staph infections, sepsis, and pneumonia, resulting in 20,000 deaths annually. Researchers at the University of Tübingen in Germany cultured the bacteria in snot samples from 37 healthy individuals, hoping to understand why vulnerability to staph infections varies from person to person. Next, they placed S. aureus alongside the different bacteria, and identified another species of staph— Staphylococcus lugdunensis—that successfully combatted S. aureus. The team then collected snot samples from 187 hospital patients, and with just one exception, found either S. aureus or S. lugdunensis in every sample, suggesting that the two cannot flourish in unison. The key compound—lugdunin—successfully treated staph infections in mice and, after leaving the two bacteria in petri dishes for a month, S. aureus was unable to develop resistance to S. lugdunensis. An ongoing outbreak of yellow fever in Angola and the Democratic Republic of the Congo has resulted in more than 5,000 cases and nearly 450 deaths. The existing vaccine against the virus is extremely effective, but is not recommended for pregnant women and those over 60 years of age. The vaccine takes a year to produce and the limited global stockpile has already been depleted twice this year. Last week, the US National Institutes of Health initiated a phase 1 clinical trial to test the safety and tolerability of an experimental yellow fever vaccine. The vaccine candidate, developed by Danish company Bavarian Nordic, uses a weakened version of the Modified Vaccinia Ankara virus as a vector to transport genes from the yellow fever virus. This delivery platform has been used in vaccinating more than 7,600 individuals, 1,000 of them immunocompromised. The trial will enroll 90 healthy volunteers, 15 of whom will receive the existing, approved yellow fever vaccine, and 75 of whom will receive one or two doses of the experimental vaccine or a placebo, with or without a booster.

TB Alliance announced last week a new agreement with Takeda Pharmaceutical Company Limited to advance novel compounds that show promise as potential treatments against tuberculosis (TB). The compounds were first identified through a recent program in which the partners screened the entirety of Takeda’s chemical library, comprised of 20,000 unique compounds. Existing TB treatment regimens can be onerous for both patients and health systems, requiring four pills per day for at least six months, and only 50 percent of patients with drug-resistant TB are cured after a two-year regimen with more toxic drugs. New drugs against TB are critically needed, and TB Alliance has not only developed multiple products, but has the largest pipeline of TB medicines in history. Both the screening program and the research moving forward are supported by the Global Health Innovative Technology (GHIT) Fund, a cross-sector partnership that invests in research and development for neglected diseases. For years, experts have known that mosquitoes are more effective at transmitting disease than a scientist with a needle, and new research suggests that the key is in the insect’s saliva. To study the impact of mosquitoes' saliva, researchers at the University of Leeds first injected a close relative of the chikungunya virus into mice, recording few symptoms and zero deaths. Next, the team allowed uninfected mosquitoes to bite the mice, and then scientists injected the virus into the mice through the site of the bite. The infection proved to be more virulent, and more than a third of the mice died. Molecules in the saliva prompt an inflammatory response, as the immune system sends neutrophils and macrophages—which combat pathogens by consuming them. The team determined that certain viruses are able to infect the macrophages, enabling the virus to replicate and travel throughout the body. Researchers at Harvard University have created a platform for rapidly and prolifically generating macrolides, a class of compounds containing some of the most common antibiotic and antifungal medicines. Macrolides were first developed in the 1950s, by tweaking microorganisms with antimicrobial properties to make them more effective and safe for use in humans. However, reliance on these natural microorganisms has made it difficult to produce new macrolides or adapt existing ones, and past efforts to develop synthetic macrolides have involved more than fifty steps—an arduous process with no guarantee that the final product will be effective. However, the team at Harvard has developed eight synthetic structures and has designed a method for rapidly combining them, and using just these eight structures and their derivatives, have created more than 300 synthetic macrolides. The team has begun to screen these macrolides for activity against different bacteria, and have identified two that are active against a bacterium that has developed resistance to vancomycin, which is considered an antibiotic of last resort. One drug candidate developed using this technique has recently been tested in two phase 3 clinical trials, proving to be effective against advanced intra-abdominal infections but ineffective against complicated urinary tract infections. The team will continue to screen the more than 300 synthetic macrolides, advancing those that prove most promising in the lab.