The term “Post-antibiotic apocalypse” may sound a little too alarmist, but it has been coined for a legitimate reason: the decreasing effectiveness of antibiotics against bacterial infections. The global misuse and abuse of antibiotics over the last 50 years has facilitated the spread and stability of resistance genes among bacterial pathogens, resulting in the emergence of multidrug resistant pathogens (also known as “superbugs”).
This phenomenon of antimicrobial resistance (AMR) is to blame for at least 700,000 annual deaths worldwide, and this number has been estimated to increase up to 10 million in 2050 (1) unless restrictive and prospective measures are adequately implemented.
Restrictive strategies intend to safeguard the viability of the current stock of antibiotics by limiting their unnecessary use, especially that of broad-spectrum ones. As an example, awareness campaigns on the risk of AMR are currently being orchestrated in several European countries as part of antibiotic stewardship programs.
Other restrictive interventions include bans on the use of antimicrobial growth promoters in livestock feed, and the development of rapid diagnostic tools to identify, for each individual infection, the etiologic agent(s) and their AMR pattern.
However, in addition to these control measures, we also need to prospectively develop new antibiotics that can replace those that are no longer effective. In a recent report (2), the World Health Organization warned that not enough candidates are being developed, with only around ten new approvals forecast to happen over the next five years. The most obvious reason for this void is that antibiotics, in comparison with other drugs, have a poor return on investment.
They are often prescribed for only a brief time to clear an infection and, because payers and reimbursers frequently work within fixed and often limited budgets, previously branded antibiotics then fall into the market of generic substitutes when patents expire. The trend for new compounds to be reserved as last resort options exacerbates this poor return on investment.
Collaborations between academic and industry research bodies is one way of developing new antibiotic candidates. Neem Biotech, a Wales-based R&D life sciences centre and fully owned Zaluvida company, has recently joined forces with Cardiff University, Innovate UK and the Welsh Government to contribute to prospectively developing new antibiotic candidates and in so doing, to contribute to the global drive towards better stewardship of antimicrobial resources.
Neem Biotech brings to this partnership its expertise in understanding and bringing together the biology and the chemistry of biologically active compounds and application of these to clinically relevant disease indications. In particular, an understanding of the bacterial quorum sensing capabilities of biofilm forming Gram negative bacteria means that Neem is currently playing its part in contributing to the global antimicrobial stewardship agenda that is one of the mainstays of the seminal O’Neill (1) recommendations.
In this set of recommendations, adjunctive therapies represent one potential way of reducing exposure to antibiotics. A reduction in the biofilm burden associated with bacteria such as Pseudomonas aeruginosa leads to enhanced susceptibility of bacteria to existing antibiotics, along with a potential concomitant reduction in the duration and volume of antibiotics required. This would give antibiotics a new lease of life and would simultaneously also reduce opportunity for further development of resistance to antibiotics.
In chronic conditions where last resort antibiotics are frequently the mainstay of treatment, curtailing of antimicrobial resistance in this way is of clear value. Ultimately, the gold standard for treatment of such conditions would, of course, be eradication of the need for antibiotics through development of disease modifiers.
In practice at the moment, however, it remains crucial that programmes aimed at discovery and development of new antibiotics are progressed in tandem with programmes tailored to support preservation of current antibiotics for as long as is feasible.
This two-pronged attack on antimicrobial resistance holds hope. Despite it being ambitious, the collaboration between Neem Biotech, Cardiff University, Innovate UK and the Welsh Government is preceded by recent success stories which demonstrate that modern technologies and approaches are slowly but surely reshaping the antibiotic discovery pipeline.
Neem Biotech is sampling different environments to look for potentially antibiotic-producing microorganisms.
In order to understand some of today’s advances, it is necessary to take a retrospective look at how antibiotics were discovered during the “golden era” (1940-1960) (3). Following a process called the Waksman platform, broad-spectrum antimicrobial compounds were selected from the systematic screening of environmental microorganisms grown under laboratory conditions until these natural scaffolds seemed to become depleted.
This methodology left uncharted not only sampling locations (like the promising deep marine environments), but also innumerable cultivation conditions. In this sense, in the last years the application of simple Waksman-like procedures in combination with more attentive cultivation conditions have rendered the characterization of new antimicrobial molecules. Examples include compounds isolated from soil microbiota (4) and commensal bacterium living in the human nose (5,6).
Furthermore, advances in sequencing technology and the increasing availability of bioinformatic tools is enabling the development of genome-based strategies to discover new antibiotics. For example, genome mining is being successfully applied to identify biosynthetic gene clusters with predicted antimicrobial activity within bacterial genome databases and metagenomic libraries (8).
Interestingly, mining of the human microbiome has so far yielded the discovery of the antibiotics produced by commensal species of the vaginal and gut microbiota as an effective response to the presence of common pathogens (9,10).
Modern genome-based approaches are taking over traditional empirical techniques such as the disk diffusion assay.
These prospective discovery strategies are just part of the creative ways scientists are undertaking to tackle AMR and develop new antibiotics. Hopefully, the need for these new drugs will be met through increasing endeavour in the form of human and funding resources, in a joined effort to put an end to this so-called “resistance era of antibiotics”.
- O’Neill (2016). Tackling drug-resistant infections globally: final report and recommendations. The review on antimicrobial resistance. https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf
- WHO/EMP/IAU/2017.12 (2017). Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, including tuberculosis. Geneva: World Health Organization; Licence: CC BY-NC-SA 3.0 IGO. http://apps.who.int/iris/bitstream/10665/258965/1/WHO-EMP-IAU-2017.11-eng.pdf?ua=1
- Brown, E. D., & Wright, G. D. (2016). Antibacterial drug discovery in the resistance era. Nature, 529(7586), 336–343.
- Wang, J., Soisson, S. M., Young, K., Shoop, W., Kodali, S., Galgoci, A., Painter, R., Parthasarathy, G., Tang, Y.S., Cummings, R., & Ha, S. (2006). Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature, 441(7091), 358-361.
- Ling, L.L., Schneider, T., Peoples, A.J., Spoering, A.L., Engels, I., Conlon, B.P., Mueller, A., Schäberle, T.F., Hughes, D.E., Epstein, S. & Jones, M., (2015). A new antibiotic kills pathogens without detectable resistance. Nature, 517(7535), 455-459.
- Kwon, H. C., Kauffman, C. A., Jensen, P. R., & Fenical, W. (2006). Marinomycins A−D, Antitumor-Antibiotics of a New Structure Class from a Marine Actinomycete of the Recently Discovered Genus “Marinispora.” Journal of the American Chemical Society, 128(5), 1622–1632.
- Zipperer, A., Konnerth, M. C., Laux, C., Berscheid, A., Janek, D., Weidenmaier, C., Burian, M., Schilling, N.A., Slavetinsky, C., Marschal, M., & Willmann, M. (2016). Human commensals producing a novel antibiotic impair pathogen colonization. Nature, 535(7613), 511-516.
- Nikolouli, K. & Mossialos, D. (2012). Bioactive compounds synthesized by non-ribosomal peptide synthetases and type-I polyketide synthases discovered through genome-mining and metagenomics. Biotechnology Letters, 34(8), 1393-1403.
- Donia, M.S., Cimermancic, P., Schulze, C.J., Brown, L.C.W., Martin, J., Mitreva, M., Clardy, J., Linington, R.G. & Fischbach, M.A. (2014). A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell, 158(6), 1402-1414.
- Chu, J., Vila-Farres, X., Inoyama, D., Ternei, M., Cohen, L.J., Gordon, E.A., Reddy, B.V.B., Charlop-Powers, Z., Zebroski, H.A., Gallardo-Macias, R. & Jaskowski, M. (2016). Discovery of MRSA active antibiotics using primary sequence from the human microbiome. Nature Chemical Biology, 12(12), 1004-1006.
About Neem Biotech
Neem Biotech is a Wales-based R&D life sciences centre that brings with it significant expertise in the biology and chemistry of bioactive compounds, and transforms these into platform technology resources for application in the fight against global threats to human and animal health.
These threats include antimicrobial resistance, metabolic disease syndrome and other areas of unmet medical needs and/or rare diseases. Particular areas of interest for Neem Biotech include cystic fibrosis, fatty liver disease and infection control in wound healing.
Neem is fully owned by the life-science group Zaluvida. Neem Biotech’s aim is to enhance the life expectancy of patients and the quality of life of both patients and their families. For further information visit: www.neembiotech.com.
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