Marine Microbial Metabolites: A new wave of drugs for Combating Antimicrobial Resistance

 

Venkat Abhiram Earny1, Venkatesh Kamath1*, Anuraag Muralidharan1, Vandana K E2, Kanav Khera3

1Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences,

Manipal Academy of Higher Education, Manipal – 576104.

2Department of Microbiology, Kasturba Medical College, Manipal Academy of Higher Education,

Manipal – 576104.

3Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences,

Manipal Academy of Higher Education, Manipal – 576104.

*Corresponding Author E-mail: venkatesh.kamath@manipal.edu

 

ABSTRACT:

The steady increase in the emergence of multidrug-resistant bacteria amongst medical centers, environment, animals, and food is of major concern for health care professionals. Most of the currently used mainline antibacterial drugs were discovered during the golden era of antibiotic discovery (1950-60). During this period, many natural, semi-synthetic, and synthetic molecules were screened for their antimicrobial potential against a spectrum of clinical pathogens. Nevertheless, there was a gap of forty long years until the release of a newer class of antibiotics in the market. It is very vital to develop an integrated approach to combat antimicrobial resistance. There has been a paradigm shift in the field of marine drug discovery in the last two decades. Bioactive metabolites derived from the marine ecosystem are known to exhibit a wide array of pharmacological activity than the terrestrial source. Among all marine organisms, secondary metabolites derived from microbes are the most underexplored natural source. Screening of marine microbes for various antimicrobial molecules has become a noteworthy trend in marine drug discovery and provides a ray of hope for combating antimicrobial resistance.

 

KEYWORDS: Antimicrobial resistance, superbugs, marine natural products, secondary metabolites.

 

 


1. INTRODUCTION:

When Penicillin entered the markets, it was a game-changer in the treatment of several life-threatening infections. Newer agents appeared through the following decades, on par with the growth of newer industries and the onset of newer diseases. These developments have revolutionized the treatment of common infections and turned the tables on therapy relating to deadly infections like pneumonia and tuberculosis. Childbirth and routine surgery could be performed with higher success rates.

 

Towards the end of the 20th century, HIV no longer remained a death sentence. It was inevitable, however, that rapid resistance to these agents, be seen in pathogens of several types and characteristics. The efficacy of life-saving drugs has however, been hampered by the emergence and spread of antimicrobial resistance. This review is an attempt to outline various metabolites with probable commercialization, obtained from marine sources, that may be used as alternatives in cases of antimicrobial resistance.

 

Resistance occurs when microbes, in their attempt to evade antimicrobials (antibiotics, antivirals, antifungals, antiparasitics), alter their characteristics to develop mechanisms that aid in their pursuit to render them ineffective. Microbes (and their evolutionary processes to sustain themselves and survive) are challenged by selective pressures arising from antibiotic usage. Several other mechanisms include mobile properties of a genome (1,2,3). The pace of discovery of novel antibiotics is far behind the rate of usage in the majority of the population. Antimicrobial resistance has become a significant concern at an international level owing to a myriad of factors that challenge the efficiency of infection and/or disease control.

 

These factors include dramatic decrease of availability of new molecules for therapeutic activity, irresponsible use of antibiotics, poor understanding of its consequences, lack of awareness about resistance in microbial strains and pathogens, excessive or unnecessary prescription of antibiotic courses and insufficient control over the use and availability to the public domain and in the production of food-producing animal, among other things. It is predicted to become the cause of 10 million deaths annually by 2050 (4). A meta-analysis involving fecal colonization brought forth sixty-six studies performed on over 28,000 healthy individuals, reporting a combined incidence of colonization with extended-spectrum beta-lactamase producers attaining 14% with a yearly surge of 5.38% (5).

 

Despite the apparent threat of antimicrobial resistance at the global level, pharmaceutical companies investing crores in research and development have been struggling to meet the need for newer antibiotics in clinical settings. The last two decades have seen lipopeptides and Oxazolidinones class of two new antibiotics against Gram-positive bacteria (6), and Gram-negative bacteria had their last novel drug class (quinolones) identification in the early 1960s. This may, however, be linked to complications in clinical development and trial workup. The lack of rapid diagnostic testing to assess the efficiency and efficacy of new antimicrobials prove to be difficult and costly. Old drug classes have been used widely in various combinations to ensure the required activity of agents, but this may result in the rapid development of resistance towards antibiotics and co-selection (7). This method of widespread use of antibiotics without proper susceptibility testing is among the many factors that result in the rise of AMR pathogens/strains (8), which affect therapeutic regimens in many disease conditions (9). This may also weaken therapeutic success rates in patients of post-operative and/or infectious disease conditions like chemotherapy for cancer or dialysis in kidney disorders, including failure. Treatment of secondary infection is decisive in surgery, particularly in cases of organ transplantation and immunosuppression. These conditions entail the use of antibiotics to protect the patient from secondary infections during periods of high vulnerability (10,11,12). Natural products or secondary metabolites are end products of a multitude of gene expressions in various microbial systems. Though they are comparatively less potent than their synthetic counterparts, they have the added benefit of better absorption and minimal side effects in natural systems. Currently, natural products from marine origin are seen as sustainable sources of secondary metabolites having antimicrobial activity against antimicrobial-resistant strains. Antimicrobial resistance, if left unchecked, may render the current drug molecules ineffective against "superbugs". The vast biodiversity of marine microbes is mirrored through chemical diversity, providing a plentiful source of biologically active metabolites.

 

2. CURRENT SCENARIO OF ANTIBIOTICS AND THEIR RESISTANCE TRENDS:

Countries that are highly prone to develop resistance towards current treatment procedures are those who already have high rates of Malaria, Tuberculosis, and HIV rates. Certain countries like India, Nigeria, and Indonesia and Russia are more at risk based on their disease profiles. If drug resistance in cases of malaria and HIV is not handled, mortality due to HIV and co-morbidity due to TB is likely to worsen in developing countries of the world, and Africa may face several unavoidable consequence.

 

In 2016, WHO came out with a priority list with names on antibiotic-resistant bacteria. This list comprised Pseudomonas aeruginosa as well as Acinetobacter baumannii resistant to carbapenem as well as Enterobacteriaceae resistant to third-generation cephalosporins. Gram-positive bacteria (high priority) included Enterococcus faecium resistant to Vancomycin and Staphylococcus aureus resistant to Methicillin. Among the organisms found to be responsible for community-acquired infections, Helicobacter pylori resistant to Clarithromycin and Campylobacter spp. resistant to fluoroquinolones, Neisseria gonorrhoeae, and Salmonella typhi are in the top-priority class. This analysis was based on criteria set by WHO, which included various aspects like mortality, health-care burden, community burden, the incidence of resistance, the 10-year pattern of resistance, preventability, transmissibility in the community setting, preventability in the health-care setting, treatability, and pipeline. The sample group of selected bacterial species consisted of 25 patterns of acquired resistance (13). However, this data has certain limitations that play a pivotal role in the assessment of the global burden. Due to the lack of global surveillance systems inactive form, significant burden and mortality linked with resistant infections cannot be calculated, and the antibiotic resistance assessment has been made from prevalence data obtained from surveillance systems that included pathogens highly prevalent in the WHO regions (14). Furthermore, India remains one of the largest consumers of antibiotics worldwide (15), and the sales of antibiotics are seen to be rising exponentially (16), in the case of cephalosporins, as compared with the other classes of drugs as they seem to be more prone to attack by resistant pathogens.

 

3. MARINE NATURAL PRODUCTS: A RAY OF HOPE TO COMBAT AMR:

Newer targets and alternative treatment methods are outlined and discussed with appropriate scientific and clinical data in another review (17) where combinatorial therapy, newer drug discovery, quorum sensing inhibition, phage therapy, and development of antibodies against virulent factors play a crucial role.

 

Other sources include isolates from environments that are minimally explored; deep-sea sources. Deep-sea habitats are vastly comprised of organisms that survive extreme conditions that may modify and evolve their adaptability and enable them to produce metabolites that are highly potent. These secondary metabolites have biological functions that aid their producers in adapting to harsh environments via efficient by-pass mechanisms to survive the unique conditions of marine life. Oceans cover about 71% of the Earth's surface and taking into consideration the water cycle, various locations of water availability, their different temperatures and salinities owing to the extreme conditions of the underwater habitats; they contain a higher amount of biodiversity and phylogenetic diversity than that present on land (18). The vast areas of the marine environment that are left unexplored and the increasing sources of microorganisms providing viable metabolites for antimicrobial activity, help classify marine natural products as one of the most appealing sources of active compounds for pharmaceutical industries (19,20,21).

 

On the contrary, there are several difficulties in exploiting marine resources. Lack of access to deep sea areas, lack of optimised growth conditions and stress factors that enable growth of potential microbes, lack of complex standard compounds for confirmatory tests of marine analogues or metabolites which may lead to wrongful confirmation of compounds based on their structural, planar, configurational aspects. This may be the reason for the approval of just six chemical compounds obtained from marine sources by the FDA in the last five decades that witnessed over 30,000 marine natural products collected and isolated, and approximately 2% of these isolates were obtained from deep-sea organisms. Deep-sea levels are still subject to debate, but a general standard states the depths to be anywhere >100m below sea level (22). However, newer screening techniques, marine sample collection methods, including standardized procedures for scuba diving to enable sample collection, are in place recently. These updates mark the steady increase in the discovery of marine natural products and their industrial significance owing to the increasing number of clinical trials harbouring potential drug compounds obtained from marine sources (23).

 

In a study conducted on two brown algae, 100 strains of endophytic actinomycetes were isolated. Out of them, 40 isolates were found to be active against clinical pathogens, and ten active strains were sequenced based on respective order of a broad spectrum of antimicrobial activity against uropathogens. Specifically, for these strains, the simulated nature of the marine environment, pH at its optimum level, low salinity, higher temperature as well as carbon-nitrogen content influences Nocardiopsis sp. GRG1 (KT235640) and showed extensive antimicrobial activity against Proteus mirabilis and Pseudomonas aeruginosa, followed by a minimum zone of inhibition against E. coli, Staphylococcus aureus, Klebsiella pneumonia. It is a significant parameter that helps to estimate the activity of newly discovered compounds against different types of pathogens — the ethyl acetate extract of the Nocardiopsis sp. GRG1 (KT235640) exhibited maximum inhibition (78 and 80%) against most uropathogens in the test group at the concentration of 100mg/ml (24).  In a similar study with endophytic actinomycetes isolated from macroalgae, MIC was checked against uropathogens at 100μg/mL and 80,77% of inhibition rate was observed against P. aeruginosa and K. pneumoniae, respectively at the concentration of 75μg/mL. The revealed antimicrobial metabolite of a certain purified fraction was primarily evaluated by microdilution assay at various concentrations (25).

 

In another study, the anti-vibrio activity of selected actinomycetes apart from their ability to produce amylase and protease enzymes was clearly demonstrated. Their findings show the definite potential of these strains as valuable "biocontrols”, and growth-enhancing agents in aquaculture industries. Although, it should be emphasized that, for Streptomyces to be considered as a probiotic and/or a growth-stimulator factor in aquaculture ecosystems, further research is of key necessity. The potent actinomycete strains isolated from the sediment of the Caspian Sea have been identified as Streptomyces using 16S rRNA sequencing followed by BLAST analysis. From the selected 21 isolates, three of them revealing prominent antibacterial activity were selected, and their morphological and physiological characteristics were determined. “Antagonistic activity of potent isolates has been evaluated against three species of Vibrio. Although bioactive metabolites produced by these three actinomycetes inhibited the growth of V. harveyi and V. proteolyticus, but MN2 isolate could not produce any biomolecule which could prevent the growth of V. parahaemolyticus(26). Additionally, all three actinomycetes were seen to produce extracellular enzymes, including amylase and protease apart from one sample: MN39, where the production of amylase was seen to be lesser, relatively.

 

 


Table 1: Novel compounds/natural products isolated from marine sources

Organism

Geographic location

Compounds/ metabolites

Susceptible pathogens

Reference

Nocardiopsis (marine derived endophytic actinomycetes) GRG1 (KT235640)

Gulf of Mannar, Rameshwaram, Tamil Nadu, India

Secondary metabolite

P. mirabilis; E. coli; S. aureus; K. pneumonia; P. aeruginosa; Enterobacter sp.; Coagulinase negative Staphylococci (MDR strains of uropathogens)

 

(24)

Streptomyces sp. (Marine-derived actinomycetes)

Al-Dhabi-90

Arabia gulf regions, Saudi Arabia

 

3-methylpyridazine;n-hexadecanoic acid

 

S. aureus; K. pneumoniae; E. coli; P. aeruginosa; P. mirabilis; Vancomycin-resistant Enterococcus faecium (VRE) (MDR and ESBL-producing clinical bacterial pathogens)

 

(27)

Nocardiopsis sp. (Marine-derived Endophytic actinomycetes) GRG2 (KT235641)

Gulf of Mannar region, Rameshwaram, Southeast coast of Tamilnadu, India

1, 4-diaza-2, 5-dioxo-3-isobutyl bicyclo [4.3.0] nonane (DDIBN)

K. pneumonia; P. aeruginosa (ESBL producers)

 

(25)

Bacillus tequilensis (MSI45)

(Bacteria from a marine sponge Callyspongia diffusa)

Vizhinjam, Kerala, Southeast coast of India

pyrrolo [1,2-a] pyrazine-1,4-dione, hexahydro

MRSA

(28)

Streptomyces coeruleorubidus GRG4 (KY457708) Marine-derived Endophytic actinomycetes

Gulf of Mannar region, Rameshwaram, Southeast coast of Tamilnadu, India

Bis (2-Ethylhexyl) Phthalate (BEP)

Colistin resistant P. aeruginosa; K. pneumonia (MDR)

 

(29)

Bacillus sp.

The great barrier reef, New Papa Guinea

Loloatin B

MRSA, Vancomycin-resistant Enterococcus faecium

(30)

Photobacterium sp.

Danish marine expedition, Galathea

Solanamidin A

MRSA

(31)

Streptomyces sp.

Jeju islands, South Korea

Anthramycin

B. anthracis, MRSA

(32)

Bacilllus sp. RJA 2194

Turnagain Island in Howe Sound, British Colombia

Turnagainolides A

MRSA, penicillin-resistant Streptococcus pneumoniae

(33)

Nocardiopsis sp.

Throndiem Fjord (an inlet of Norwegian sea), Norway

Triopeptide TP-1161

Vancomycin-resistant Enterococcus faecium

(34)

Daldinia eschholzii (Marine sponge derived fungus)

Karimunjawa National Park, Central Java, Indonesia

Karimanone (Chromanone type)

Salmonella enterica ser. Typhi (MDR)

 

(35)

 

 


4. CONCLUSION:

Discovery rate of new active metabolites that may potentially be antimicrobial compounds, from particular marine microorganisms is increasing, and considering these as important sources of new antibiotic molecules may result in possible new lead compounds. This is with an understanding that finding newer chemical structures is the initial step in drug development processes. A number of factors, however, confine the development of drugs from natural origin. This may be overcome by firstly procuring a stable and sustainable supply of new chemical structures from the marine environment by optimising collection strategies, development of fermentation protocols, recombination methods, chemical synthesis, and methods employed to guarantee production of desirable compounds in sufficient amounts and purity parameters. The next step includes an analysis of ADMET properties of the chemical moieties.

 

These studies aim to optimize the drug compound during administration to reduce or avoid toxicity and minimize the risk of resistance when coupled with structural activity relationship (SAR) studies. Antimicrobials and combinatorial therapy may remain viable for quite some time, but the advancement of microorganisms in terms of resistance patterns due to environmental stress is a process well beyond our scope of expertise. Although managing and manipulating microbiota is a valid option, it is more preventive than curative in nature. However, more studies need to be performed to dwell on the alternatives and recent advancements in technology to develop more suited drug molecules for the efficient treatment of resistant strains of microorganisms. The vast expanse of the marine environment that has been left unexplored may prove to be the source of novel strains with potent activity to effectively handle antimicrobial-resistance.

 

5. ACKNOWLEDGEMENT:

The authors are thankful to Manipal Centre for Infectious Diseases (MAC ID), MAHE and Manipal College of Pharmaceutical Sciences, MAHE for their support and assistance.

 

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Received on 24.04.2020            Modified on 05.06.2020

Accepted on 20.07.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(4):2348-2352.

DOI: 10.52711/0974-360X.2021.00414