The search for a solution to antimicrobial resistance found something. And researchers found it in a true “it’s always the last place you look” location.
Australian oysters. Or more specifically, Australian oyster blood.
We know antimicrobial resistance claims at least 1 million lives each year, and experts suspect that number to double by 2050. To that end, a team of scientists in Australia set out to explore antibiotic alternatives by observing the antibacterial activity of a semi-purified hemolymph protein extract (HPE) from the Sydney rock oyster or Saccostrea glomerata. Their findings were published in PLOS One.
Why Oysters?
It begins with antimicrobial proteins and peptides (AMPPs) — among the most promising pharmacological leads in the fight against antimicrobial resistance.
This research team had already investigated AMPPs of marine invertebrates, particularly mollusks. Invertebrates such as mollusks do not have an acquired immune system and, therefore, do not produce antibodies to respond to pathogens. Despite this, they thrive in a wide range of microbially rich habitats.
“I thought [mollusks] must have some strong antimicrobial compounds in their hemolymph (blood) to compensate, especially filter-feeding mollusks like oysters that are constantly pumping bacteria through their gills,” said Kirsten Benkendorff, professor and director of the National Marine Science Centre, Southern Cross University, Coffs Harbour, Australia, and the supervisor of this study.
Under Benkendorff’s supervision, lead researcher Kate Summer screened the hemolymph of several mollusk species and referred to Benkendorff’s postdoctorate on molluscan egg masses. Benkendorff had found an antibiotic in the whelk egg capsules: Not an antimicrobial protein or peptide but another organic compound, a small brominated indole.
Along with the mollusk hemolymphs, Summer observed the brominated indoles. Benkendorff had previously isolated against the respiratory pathogen for pneumonia, Streptococcus pneumoniae. The Sydney rock oyster’s hemolymph had exhibited the strongest, most reproducible activity.
“We published a preliminary paper that characterized the antibacterial activity of the Sydney rock oyster hemolymph and protein fractions against S pneumoniae in Marine Biotechnology,” said Benkendorff. “The PLOS One paper built on this work by testing the antibacterial and antibiofilm activity of the active AMPP fraction against three clinical strains of S pneumoniae, as well as six other respiratory pathogens.”
What They Found
Summer and the team of researchers tested the oyster’s AMPP in combination with conventional antibiotics (ampicillin, gentamicin, trimethoprim, and ciprofloxacin), noting that at low concentrations, the effectiveness of these antibiotics improved between 2- and 32-fold. The combination therapy was especially effective against golden staph infections, Staphylococcus aureus and Pseudomonas aeruginosa infections. (Those with autoimmune conditions are most susceptible to these.)
“On its own, the oyster AMPP showed specific activity toward [the] Streptococcus species,” said Benkendorff. “However, when used in combination, a lower dose of both the oyster AMPP and conventional antibiotics was required to kill a range of respiratory pathogens. This implies the oyster AMPP has a different mode of action to the conventional antibiotics, possibly by penetrating biofilms and cell walls to make the antibiotics more available to the cells.”
Almost all bacterial infections have biofilms, a self-secreted, slimy substance made up of millions of bacterial cells that protect them from a host’s immune system and antibiotics.
On top of antimicrobial resistance, pneumonia and other respiratory infections are difficult to treat due to their biofilm formations, which explains how they have been able to persist as a leading cause of hospitalization and death among children and older adults. Summer and her team found that the oyster AMPPs could not only penetrate already-formed biofilms in Streptococcus spp. bacteria but also stop the biofilm from forming in the first place.
The oyster AMPPs also exhibited no toxic effects to human lung cells, further demonstrating their potential as an effective, safe possibility in the development of new antimicrobial agents and combination therapies. Oyster AMPPs specifically can help combat existing antimicrobial resistance and lower its evolutionary rate as the lower combined doses of oyster AMPPs and antibiotics reduce the overall exposure to and reliance on antibiotics.
“AMPPs are an exciting area with a lot of potential,” said Shauna McGillivray, PhD, a professor of biology at Texas Christian University, Fort Worth, Texas, with an emphasis on host-pathogen interactions. “[They] are by themselves very potent but, as has been noted in multiple studies, they can also synergize with existing antibiotics, thereby improving efficacy of antibiotics, even in some cases to antibiotics to which there are high levels of resistance.”
McGillivray, who was not involved in the research, pointed out that development of resistance is generally low and less than the resistance seen with conventional antibiotics. However, she said, “low resistance does not mean no resistance, and there is evidence that bacteria can evolve resistance to AMPPs. Using AMPPs from nonhuman sources is smart because it expands the potential AMPPs available to develop and, if resistance does develop, could help minimize unintended consequences such as resistance to the naturally produced host AMPPs.”
What Comes Next
Of course, additional research is needed. Questions regarding the influence of oyster condition and sampling time (as determined by climate, season, water quality, and organism life cycle) on AMPP activity remain unanswered.
While Summer was able to isolate and identify the oyster’s HPE via high-performance liquid chromatography and associate antibacterial and antibiofilm activity with one main fraction containing a mix of proteins, these proteins require further purification to test individually and in combination.
The mix of proteins observed mostly included housekeeping-type proteins. “Only a few proteins are possible AMPP candidates based on their presence in active fractions,” said Benkendorff. Cystatins were the most abundant AMPPs present in HPE, but more studies are needed to test them in combination with antibiotics.
The good news: If a drug can be developed from the Sydney rock oyster’s HPE, the research team are even hopeful about maintaining the oyster population. “[T]he Sydney rock oyster can be produced on a large scale by aquaculture, so it will be possible to produce sufficient quantities for preclinical and clinical trials,” said Benkendorff. “If these trials are successful, alternative methods for large-scale biosynthesis could be developed through genetic engineering.”
McGillivray maintains that research like this should remain a priority. “We are at a critical juncture when it comes to antimicrobial resistance, and investment in new antibiotics is needed now,” she said. “Antibiotics revolutionized medicine, but unfortunately, we have taken them for granted.”