A marine molecule that is effective against MRSA, VRE, Anthracis bacillus and other Gram-positive microorganisms

Multiple Resistant Staphylococcus aureus (MRSA)

Marinus Hospital-Operating-RoomMulti-drug resistant (MDR) bacteria potentially pose a significant risk to people in the United States and all over the world; at the moment, the risk is the greatest where antibiotics are most commonly taken. The most notable MDR organisms are Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus faecium (VRE) and Carbapenem-resistant Pseudomonas aeruginosa. All three are associated with nosocomial infections.

No population is more vulnerable to multi-drug resistance that those admitted to hospital wards. In the United States alone, 14,000 individuals are infected and die each year from hospital acquired multi-drug bacteria. MRSA, specifically community acquired MRSA (CA-MRSA), has emerged as a significant and growing health threat to the public at large. CA-MRSA has acquired increased virulence and pathogenicity and it increasingly causes aggressive infections in young, healthy people.

Current Antibiotics in Clinical Use

The major antibiotics in current clinical use were discovered by screening terrestrial microorganisms. Over the past decade, however, the discovery rate of new antibiotics from terrestrial sources has decreased. At this time, the dereplication rate for the terrestrial environment is estimated to be greater than 90%.

The Marine Environment as a Potential Source of New Antibiotics

In contrast, the marine environment represents a relatively unexplored resource for the discovery of new antimicrobial compounds. The extreme diversity of the marine environment with respect to salinity, temperature, pressure and nutritional availability provides an environment that selects for a high level of genetic and molecular diversity among the microorganisms that exist there.

Marine microorganisms have developed unique metabolic and physiological properties that allow them to survive in these extreme environments. Marine bacteria have the ability to incorporate halogens (Br, Cl, F and I) found in high concentrations in seawater into secondary metabolites. This is important because many antimicrobial compounds are halogenated. The marine environment is therefore likely to be a good source for new antimicrobials.

Marinus Sponge
Marinus Marine-Microorganisms

Anti-MRSA Hits from Marine Microorganisms

Aphios has established a library of more than 2,000 unique marine microorganisms from diverse environments, including deep-sea sediments to shallow water mangrove swamps, tropical waters to temperate oceans, hydrothermal vents and hypersaline ponds as well as from sponges, corals and other marine invertebrates. Aphios has also developed proprietary fermentation techniques that mimic the natural saline marine environment in order to enhance isolation of bioactive compounds and allow large-scale manufacture of novel anti-infectives and anticancer drugs. The microorganisms (bacteria, actinomyces, yeasts and fungi) are fermented in at least four different media designed to maximize the diversity of secondary metabolites being generated.

In our research to date, 4,800 fractions of 400 marine microorganisms were utilized as a starting point for a systematic search for the discovery of antimicrobial compounds. The ability of the fractions to inhibit the growth of two Gram-positive bacteria, Streptococcus mutans and Actinomyces viscosus, were evaluated in 96-well format using a plate reader and visually confirmed.

Marinus Growth-Inhibition-of-MDR-E.-faecium smTwelve potential "hits" which exhibited greater than 95 % inhibition of growth of these two organisms were tested for inhibition of growth against MDR Staphylococcus aureus ATCC 33592 (gentamicin and methicillin) and Enterococcus faecium ATCC 51559 (ampicillin, ciprofloxacin, gentamicin, rifampin, teicoplanin and vancomycin). Activity was determined based on inhibition of cell growth relative to a viability control on the same plate.

Six marine microorganism fractions that showed greater than 25 % inhibition of one or both of these organisms were tested for minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The most active fraction, with an absolute purity < 0.1%, had MICs of 15.6 μg/mL and 3.9 μg/mL and MBCs of 31.25 μg/mL and 15.63 μg/mL respectively against MDR Staphylococcus aureus and Enterococcus faecium.

Partnering Opportunity

In our next steps, saline fermentation will be scaled-up to manufacture sufficient MDR compound(s) for further studies and competitively compared to synthesis and/or semi-synthesis of these compounds. Mechanism of action and SAR studies will then be conducted followed by medicinal chemistry to maximize effectiveness and minimize toxicity against MDR bacteria. The anti-MDR compound(s) will be tested against MDR clinical isolates of Staphylococcus aureus and Enterococcus faecium and competitively evaluated in ADME studies.

The development of Marinus™, a marine molecule that is effective against MRSA, VRE, Anthracis bacillus and other Gram-positive microorganisms could eventually result in providing much-needed drugs for susceptible patients while addressing a $44 billion worldwide market for fighting infectious diseases.

We are seeking a strategic multinational pharmaceutical partner for the development and commercialization of our lead anti-microbial MDR compounds.

White Paper

Interested in reading more? Request this white paper.