“Microbes Against Microbes”; Exploitation and Use of Microorganisms for Treatment of Infections

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By Jimmy Nkaiwuatei

For Correspondence: jimmynkaiwuatei@gmail.com

Introduction

The emergence of Antimicrobial Resistance (AMR) has become a huge global health burden. In 2019 alone, the number of deaths associated with bacterial antimicrobial resistance was approximately 4.95 million, with 1.27 million deaths directly attributable to bacterial antimicrobial resistance, and western Sub-Saharan Africa was hardest hit by this health threat at 27.3 deaths in a population of 100,000 people1. The discovery and development of antimicrobial drugs were one of the last century’s remarkable discoveries in medicine and several lives have been saved because doctors were able to treat the infections unlike in the pre-antibiotic era. Microorganisms do naturally mutate through natural selection, and when they get in contact with antimicrobial drugs, they develop mechanisms of antimicrobial resistance by mutating into new forms to counteract the actions of these drugs2.

Research and invention of new novel antimicrobial drugs is urgently needed to fill the almost dry pipeline of antibiotics, and ultimately prevent the development of antimicrobial resistance. Pharmaceutical industries should be incentivized to boost their research capacities against antimicrobial resistance3. Although most microorganisms cause disease to humans, some are useful, and they are either directly or indirectly beneficial. For instance, they are used as probiotics, production of recombinant antimicrobial drugs and vaccines, sources of antimicrobial peptides, as well as bacteriophages that kill bacteria4.

Probiotics

Probiotics are live microorganisms that, when adequately administered, produce beneficial effects on the body5. They prevent infections by inhibiting the pathogenic bacteria by secreting antimicrobial metabolites such as bacteriocins, organic acids, hydrogen peroxide di-acetyl, and acetoin6. Probiotics have been found to be effective against bacterial biofilms and have been used in the prevention of food spoilage because of their inhibitory effect against bacterial growth6. Biofilms are a complex association of microorganisms that forms on surfaces and are protected by complex polymers of extracellular polysaccharides which can prevent the microorganisms from destruction by harsh chemicals such as antimicrobial agents, thus facilitating the development of antimicrobial resistance7. Lactic acid bacteria are good examples of probiotics that have been used in the prevention of adhesion of bacterial pathogens on surfaces hence preventing biofilm formation8.

Recombinant production of antimicrobial agents

Recombinant DNA technology has been successfully used in the production of antimicrobial peptides, drugs, and vaccines. This involves two main processes: upstream and downstream9. Upstream processes include cell lysis, fermentation, construction of a plasmid, host transformation, selection of transformed cells, and production of the transformed cells in the host, while the downstream ones involve the harvesting of the transformed cells, separation of cell debris and media components, concentration, bio-conjugation, purification, protein characterization, and refolding9. E. coli has been largely used in recombinant DNA technology due to its ease of manipulation10. Generally, the genes that code for antimicrobial peptides in the source organisms (mammals, bacteria, fungi, arthropods, and insects) are isolated and inserted in a microorganism (E. coli) where the protein of interest will then be expressed and produced in large quantities, harvested and finally purified for use in treatment11.

Antimicrobial peptides (AMPs)

Antimicrobial peptides are small protein compounds that are useful in the inhibition of various types of microorganisms5. They have the potential to elicit the host’s immune response, as well as act as the first line of defense by stimulating angiogenesis and chemokines. Interestingly, they portray a broad spectrum of activity against various types of microorganisms and can be found in bacteria, vertebrates, invertebrates, and plants12.

Large AMPs which consist of approximately, 100 amino acids act by causing bacterial lysis, binding to nutrients, or targeting specific macromolecules in bacteria, while the small ones act by interfering with the function and structure of bacterial cell membranes or by directly causing bacterial enzymatic interference by interacting with Adenosine Triphosphate (ATP)13.

Isolation of antimicrobial peptides from bacteria and subsequent antimicrobial activity assay can be achieved through the following general techniques: bacterial lysis, protein separation, purification, concentration, and finally microbial inhibition assay14.

For instance, isolation and purification of antimicrobial peptides from Saccharomyces boulardii have been achieved using sonication (cell lysis), and ultrafiltration through dialysis membranes (purification), respectively14. Then the microbial inhibitory effect can be assayed by subjecting the purified peptides on the pure colonies of the microorganisms to being tested.

Bacteriophages

Bacteriophages are viruses that can attack and kill specific species of bacteria. They do so through either lytic or lysogenic cycles9. In a lytic cycle, after attachment and penetration into the bacterial cells, the bacteriophages introduce their genetic material into the host’s cytoplasm and replicate using the host’s ribosomes, leading to lysis and death of the bacteria, releasing phages that attack other bacteria of the same species. In a lysogenic cycle, the bacteriophages penetrate into the bacterial cell, and integrate their DNA into the host’s chromosomes where they continue to replicate and are passed on to the bacterial daughter cells without killing them9.

Conclusion

In the search and development of antimicrobial agents, microorganisms also play a pivotal role. They can be utilized either directly to provide defense against invasion by other infectious agents or indirectly as tools of production of anti-infective agents. Microorganisms are so vast in nature, and they should therefore be explored in order to innovate potential and effective therapeutics against infections including drug-resistant ones.

The pipeline for antimicrobials research, discovery, and development is almost dry. This is attributable to the failure of pharmaceutical companies to focus their investments in the research and development of these drugs due to the high cost involved in the production and a low-profit turnover. This coupled with the fact that most of the currently available antimicrobials are rendered ineffective by the emerging superbugs, facilitates the acceleration of antimicrobial resistance. Therefore, pharmaceutical companies should highly commit their efforts in research and innovation of effective alternative therapies against microbial infections. In addition, national governments and funding organizations should provide antimicrobials subscription models such as delinked pull incentives both to individual drug researchers and pharmaceutical companies to cushion them from the high costs involved in antimicrobial research and development.

There is an urgent need to employ these and other innovative approaches to increase research and development, as well as access to novel antimicrobials, especially in the low-resourced settings such as Africa.

References

1Lancet, collaborators, Antimicrobial Resistance. 2022. “Articles Global Burden of Bacterial Antimicrobial Resistance in 2019 : A Systematic Analysis” 399. https://doi.org/10.1016/S0140-6736(21)02724-0.

2Aminov, Rustam I. 2010. “A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future.” Frontiers in Microbiology 1(DEC)/. pmc/articles/PMC3109405/ (March 27, 2022)2.

3Elhag, Osama et al. 2017. “Screening , Expression , Purification and Functional Characterization of Novel Antimicrobial Peptide Genes from Hermetia Illucens “(L .).” : 1–15.

4Ghosh, Chandradhish, Paramita Sarkar, Rahaf Issa, and Jayanta Haldar. 2019. “Alternatives to Conventional Antibiotics in the Era of Antimicrobial Resistance.”Trends in Microbiology 27 (4): 323–38. https://doi.org/10.1016/J.TIM.2018.12.010.

5Hassan, M. et al. 2012. “Natural Antimicrobial Peptides from Bacteria: Characteristics and Potential Applications to Fight against Antibiotic Resistance.” Journal of Applied Microbiology 113(4): 723–365.

6Šušković, Jagoda et al. 2010. “Antimicrobial Activity – The Most Important Property of Probiotic and Starter Lactic Acid Bacteria.” Food Technology and Biotechnology 48(3): 296–307.

7Meroni, Gabriele et al. 2021. “Probiotics as Therapeutic Tools against Pathogenic Biofilms: Have We Found the Perfect Weapon?” Microbiology Research 12(4): 916–37.

8Prabhurajeshwar, C., and Kelmani Chandrakanth. 2019. “Evaluation of Antimicrobial Properties and Their Substances against Pathogenic Bacteria In-Vitro by Probiotic Lactobacilli Strains Isolated from Commercial Yoghurt.” Clinical Nutrition Experimental 23: 97–115. https://doi.org/10.1016/j.yclnex.2018.10.001.

9Kasman, Laura M., and La Donna Porter. 2021. “Bacteriophages.” Brenner’s Encyclopedia of Genetics: Second Edition: 280–83. https://www.ncbi.nlm.nih.gov/books/NBK493185/ (March 27, 2022).

10Li, Yifeng. 2011. “Recombinant Production of Antimicrobial Peptides in Escherichia Coli: A Review.” Protein expression and purification 80(2): 260–67. https://pubmed.ncbi.nlm.nih.gov/21843642/ (March 26, 2022).

11Tanhaiean, Abass et al. 2018. “Recombinant Production of a Chimeric Antimicrobial Peptide in E. Coli and Assessment of Its Activity against Some Avian Clinically Isolated Pathogens.” Microbial Pathogenesis 122(April): 73–78. https://doi.org/10.1016/j.micpath.2018.06.012: 296-307.

12Zhang, Qi Yu et al. 2021. “Antimicrobial Peptides: Mechanism of Action, Activity and Clinical Potential.” Military Medical Research 8(1).

13Lei, Jun et al. 2019. “The Antimicrobial Peptides and Their Potential Clinical Applications.” American Journal of Translational Research 11(7): 3919. /pmc/articles/PMC6684887/ (March 26, 2022).

14Naimah, Alaa Kareem, Alaa Jabbar Abd Al-Manhel, and Manar Jabbar Al-Shawi. 2018. “Isolation, Purification and Characterization of Antimicrobial Peptides Produced from Saccharomyces Boulardii.” International Journal of Peptide Research and Therapeutics 24 (3):455–61. https://doi.org/10.1007/S10989-017-9632-2.

About the Author: Jimmy Nkaiwuatei recently completed a Bachelors in Biochemistry at Jomo Kenyatta University of Agriculture and Technology. He is the Head of Drug Research and Discovery at Students Against Superbugs Africa and has been at the forefront of advocating for the active inclusion of students and early career professionals in the research and development of new diagnostics and therapeutic interventions to mitigate Antimicrobial Resistance.

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