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Posted by Megan on June 13th, 2017 in Megan Hardie  ⟩  0 comments

The overuse of antibiotics has been debated in the biochemical and medical fields for decades, concern peaking in the last ten years as previously effective antibiotics prove increasingly obsolete against bacterial evolution. Opportunistic microbes can retaliate against our medicine faster with each generation; we produce innovative ways to combat them, but it’s a constant race for advancement.

This conflict has been deemed a crisis by experts and even the beginnings of an “antibiotics apocalypse.” Consequences go beyond an incurable case of Staphylococcus or E. coli – surgical procedures would become infinitely more life-threatening, and the danger of food shortages from infections in livestock would also pose complications. If allowed to continue their rampant evolution, our bacterial adversaries (as opposed to those who benefit us, like our microbiome) could make injuries as innocuous as papercuts potentially lethal.

In response to the bacterial uprising, the Infectious Diseases Society of America (IDSA) proposed in 2010 a “10 x ‘20” initiative that encouraged the scientific community to circumvent any such apocalyptic outcome. They stated that by 2020, it was in the best interests of the U.S. government and pharmaceutical sector to research and produce 10 new and effective antibiotics. Since the late 1980s, no such inventions had occurred.

To assess if research has taken the initiative to relieve our anxiety, we must first address what developments have transpired in the bacterial world following the mass-production of antibiotics. 



The Rise of an Antibacterial Apocalypse

Antibiotics can become outdated after their initial application in medicinal settings. Dispensed through prescription and over-the-counter purchases, they’re easily accessible and often depended on by those experiencing illnesses symptomatic of bacterial infection. Penicillin was the first weapon against such disease, but it eventually lost effectiveness against resistant strains of bacteria. Those strains then surpassed yet other classes of antibiotics. Contemporary statistics from the Center of Disease Control and Prevention report that tens of thousands die annually in the U.S. and Europe from such “resistant,” untreatable bacteria.

Higher grade antibiotics are used even more frequently in developing countries due to the cost of identifying diseases; to be certain a patient will survive, the most effective antibiotics are prescribed and thus lose their potency more rapidly. Strains of Staphylococcus aureus and E. coli bacteria associated with the waste of a hospital in India have shown upwards to complete resistance against over half a dozen antibiotics. In a laboratory setting, pathogens like E. coli have been isolated and studied in laboratory environments to reveal resistance to colistin and even MDR antibiotics like carbapenem. 

Antibiotic treatment was later introduced to food production and the veterinary profession. Contamination of the environment from waste products in these facilities contributes to the oversaturation of antibiotics in our surroundings, allowing bacteria to evolve under the rug through environmental selection. The speed of antibiotic futility increases steadily, but the expense of clinical trials, sluggish approval of new drugs and caution from pharmaceutical industries makes it harder for new antibiotics to become widely available.





Progress and New Discoveries

It’s obvious that the human race will benefit from an expansion of our antibiotic registry. So what progress has been made?

Recent input from Antibiotic Action and Sally Davies, England’s Chief Medical Officer, proved convincing to government officials in England. Developing strategies against bacterial resistance has become a major topic among the country’s government officials. Their Department of Health agreed to publish a five-year “Antimicrobial Resistance Strategy.” This plan promotes both the “responsible use of antibiotics” and “development of new diagnostics, therapeutics and antibiotics” for use in the medical field.

In the U.S. and globally, the IDSA has made further recommendations to its “10 x ‘20” goal. The association has sent advocacy letters to the World Health Organization, U.N., and the Trump administration at the end of 2016 and early 2017 urging continued support for antibiotic innovation programs. They likewise raised awareness to implement the Strategies to Address Antimicrobial Resistance (STAAR) Act, legislation similar to England’s Antimicrobial Resistance Strategy. The Food and Drug Administration and CDC, which has noted the appearance of “nightmare bacteria” in new strains, are also participating in campaigns for increased attention to this research.

Trial testing for new antibiotics is a growing feature of medical research. By March of this year, 41 antibiotics were undergoing clinical trials: two NDA submissions, 15 Phase 1 trials, 13 Phase 2, and 11 Phase 3. Many new substances are expected to act against resistant gram-negative ESKAPE pathogens and CDC "urgent threat" pathogens. None of these drugs are guaranteed to qualify beyond trials, but their inclusion in the research process is promising.

Experimentation in 2015 demonstrated persistent microbes being exterminated by teixobactin, isolated from an uncultured bacterium E. terrae. In the laboratory setting, teixobactin bound to conserved motifs of lipid II and III, inhibiting the synthesis of cell walls in bacteria and causing cell lysis. Teixobactin proved effective against pathogens already displaying drug-resistance. Results predict that it would take 30 years for bacteria to develop resistance against this class of antibiotics.

Boromycin – a boron-containing polyether macrolide antibiotic derived from Streptomyces antibioticusshowed similar results in 2016. Because of their lower rates of selectivity, ionophores like boromycin are used in veterinary medicine but not human treatments. Researchers claimed boromycin was “a potent, submicromolar inhibitor of mycobacterial growth with submicromolar bactericidal activity against growing and non-growing drug tolerant persister bacilli.” When injected into a sample of B. subtilis, it induced a collapse of the microbes’ potassium gradients. Results from tests with M. bovis demonstrated boromycin’s ability to hinder mycobacteria as well as gram-positive types. Its effect on membrane polarization also reduced ATP in the bacteria and caused cell lysis. Resistant mutations were not detected. These are all positive attributes to boromycin’s antibiotic resume, raising the possibility it could transition to human medicine.

Another research project displayed the benefits of alternative resources for extinguishing bacteria. February of this year, a speaker at the American Association for the Advancement of Science presented test results on the use of inorganic silver nanoparticles (AgNP) merged with an antibiotic, streptomycin. The experiment against E. coli microbes sought to determine if the addition of silver reduced resistance development. The results were encouraging: AgNP inhibited E. coli growth, and its partnering with streptomycin lengthened the suppression period of E. coli generation. This method is especially exciting, because lowering the concentration of antibiotics used in treatment would demote bacterial resistance mutation.

Future Projections

With the “10 x ‘20” goal unmet as of 2017, has the campaign for new antibiotics stagnated? No – with so many dedicated scientists and organizations funding the coordination of this research, it’s clear there has been and will be progress. Science does not operate on deadlines, and it cannot be known when the next breakthrough might surprise us from the petri dish of an unsuspecting graduate student.

Still, the questions remain: when will we discover new antibiotics, and why has it not happened yet?

There is danger in lagging behind bacterial advancement. A recent project at Harvard has shown the possible damage of antibiotic resistance if it is not reduced to a microscopic size: an estimated ten million could die in the next three decades if no progress is made against rising frequencies of resistant bacteria. Similar projections were made by Jim O’Neill, who predicted additional ten million casualties annually starting in 2050 if the post-antibiotic apocalypse occurred. O’Neill made suggestions to refrain from abusing current antibiotics by reducing use in agriculture and medicine. He also advocated educating the public on their responsibility to the movement through alternatives like routine vaccinations.

Bacteria do not procrastinate. To preserve the current state of global health, we must get an advantage over the pathogens present in our daily environment. It’s unrealistic to assume a breakthrough will occur autonomously – the scientific community is depended upon to produce it. Our knowledge and equip is ever-increasing in its capability to innovate against the biological threats of past centuries. The necessity of testing continues. Formulating new drugs in the next three years is crucial if we are to achieve or surpass the original "10 x '20" goal. This global affair takes the cooperation of labs, the scientific community, and contributors across the board to create a safety blanket for our generation and those to come. 

References

British Society for Antimicrobial Chemotherapy. (n.d.). Antimicrobial resistance poses 'catastrophic threat', says Chief Medical Officer. Retrieved June 07, 2017, from http://bsac.org.uk/antimicrobial-resistance-poses-...

Call, D. R., Matthews, L., Subbiah, M., & Liu, J. (2013). Do antibiotic residues in soils play a role in amplification and transmission of antibiotic resistant bacteria in cattle populations?. Frontiers in microbiology, 4(193). doi:10.3389/fmicb.2013.00193.

Center for Disease Control and Prevention. (2017, April 10). Antibiotic Resistance Threats in the United States, 2013. Retrieved June 07, 2017, from https://www.cdc.gov/drugresistance/threat-report-2...

Divya, S., Jessen, G., Divya, L., Naz, A. R., Midhun, G., & Suriyanarayanan, S. (2016). Antibiotic Resistance Patterns of E. coli and Staphylococcus aureus Isolated from Hospital wastewater samples of Mysore, Karnataka, South India. Bulletin of Environmental and Scientific Research, 5(3-4).

Ling, Losee L. et al. (2015). A new antibiotic kills pathogens without detectable resistance. Nature, 517(455-459). doi:10.1038/nature14098.

Moreira, W., Aziz, D. B., & Thomas, D. (2016). Boromycin Kills Mycobacterial Persisters without Detectable Resistance. Frontiers in Microbiology, 7, 199. doi:10.3389/fmicb.2016.00199.

The PEW Charitable Trusts. (2016). [Antibiotics Currently in Clinical Development]. Retrieved June 07, 2017, from hhttp://www.pewtrusts.org/~/media/assets/2017/05/antibiotics-currently-in-clinical-development-03-2017.pdf?la=en

Pas, S. (2017, February 17). Reducing Antibiotic Resistance and MIC Using Silver Nanoparticles with Antibiotics. Lecture presented at AAAS 2017 Annual Meeting in Exhibit Hall (Hynes Convention Center), Boston.

Poirel, L., Kieffer, N., Liassine, N., Thanh, D., & Nordmann, P. (2016). Plasmid-mediated carbapenem and colistin resistance in a clinical isolate of Escherichia coli. Lancet Infect Dis, 16(281). doi:10.1016/S1473-3099(16)00006-2.

Smith, O. (2017, March 20). Antibiotic Apocalypse: Harvard reveals doomsday scenario that could kill 10 million a year. Retrieved June 07, 2017, from http://www.express.co.uk/news/world/781168/Harvard...

Thakuria, B., & Lahon, K. (2013). The Beta Lactam Antibiotics as an Empirical Therapy in a Developing Country: An Update on Their Current Status and Recommendations to Counter the Resistance against Them. Journal of Clinical and Diagnostic Research, 7(6), 1207-1214. doi:10.7860/JCDR/2013/5239.3052.

Yong, E. (2016, May 19). The Plan to Avert Our Post-Antibiotic Apocalypse. Retrieved June 07, 2017, from https://www.theatlantic.com/science/archive/2016/0...

(Antibiotic Fall from Grace; Development of New Antibiotics Countdown)


               Megan Hardie
         GoldBio Staff Writer     

Megan Hardie is an undergraduate student at The Ohio State
University’s Honors Arts and Sciences program. Her eclectic
interests have led to a rather unwieldly degree title: BS in
Anthropological Sciences and BA English Creative Writing,
Forensics Minor. She aspires to a PhD in Forensic Anthropology
and MA in English. In her career, she endeavors to apply the
qualities of literature to the scientific mode and vice versa,
integrating analysis with artistic expression.

 

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