Welcome Back to the Pre-Penicillin Era. Why We Desperately Need New Strategies in the Battle Against Bacterial Pathogens : Infectious Microbes & Diseases

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Welcome Back to the Pre-Penicillin Era. Why We Desperately Need New Strategies in the Battle Against Bacterial Pathogens

Leptihn, Sebastian1,2

Editor(s): van der Veen, Stijn

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Infectious Microbes & Diseases: December 2019 - Volume 1 - Issue 2 - p 33
doi: 10.1097/IM9.0000000000000009
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In 2023, one hundred years will have passed since penicillin was discovered. My parents’ generation was born around the time penicillin was introduced (in 1942), raising their children when the last class of antibiotics was introduced (Daptomycin in the late 1980s), and recently saw major players of the pharmaceutical industry abandon their research programs on novel antibiotics.1,2 In the span of one lifetime, mankind has experienced the tremendous success of antibiotics and the realization of the horrific consequences of their failure, with over 10 million deaths predicted by 2050 due to multidrug-resistant infections.3 With the rise of multidrug-resistant pathogens, resistant to many if not all compounds, it seems the golden era of antibiotics has lasted less than one century.

With more than 3.8 billion years of prokaryotic evolution,4 we erroneously believed that the products of our synaptic neurochemistry were a match for the bacterial world, but we were wrong. We are part of a complex ecosystem with approximately 1030 prokaryotic cells5 (more than there are stars in the universe!) that rapidly exchange genetic information. Critical factors such as DNA uptake mechanisms, lateral gene transfer (via conjugation) and the help of ten times more viruses than prokaryotic cells combined with fast generation times and high mutational rates make the spread of antibiotic resistance genes efficient and rapid, far more so than our limited attempts to generate a new arsenal of weapons against the microbial world. Indeed, if microbes could laugh, they would.

Despite their intricate sophistication and complexity, the pathogens we fear have not themselves been our worst enemy – we have brought this crisis upon ourselves by overprescribing, overusing, and misusing antibiotic drugs. We have willfully destroyed our own arsenal and facilitated the emergence of a full spectrum of antibiotic resistance to occur. It is horrific to contemplate re-entering the pre-penicillin era, to travel back to a time when an infected cut in your skin could be a death sentence. Yet there is hope. Promising new strategies have and are being developed and are gaining growing attention from the urgent need for new weaponry against bacterial pathogens. Two beautiful examples come from nature itself; antimicrobial peptides (AMPs) and bacteriophages (viruses of microbes). AMPs are short peptides that can interact with the membranes of bacterial species but not with the membranes of eukaryotic cells, due to fundamental differences in membrane composition and architecture.6 AMPs are deployed as the first line of defense within our innate immune system and we can create novel AMPs that are efficient and safe to use and deploy (if obstacles such as production cost and any adverse properties of such peptides can be overcome). After infection and replication, lytic bacteriophages kill their host by lysis, that is, the destruction of the cell wall. This phenomenon is being utilized in phage therapy, where a solution of the phage is administered to a patient suffering from a bacterial infection.7 The phages will infect the disease-causing bacterium, eventually leading to pathogen elimination. For phage therapy to become standard clinical practice, many obstacles will need to be overcome including the rapid identification – or matching of phage to bacterial host (since phages are often strain specific) and the complex interplay between phages and our immune system.

Now is not the time to be timid in our search for solutions to our present antimicrobial crisis. With the plethora of scientific knowledge available and the ingenuity of the human mind, let us hope that our search, like evolution, will not crawl, but leap forward.


1. Lepore C, Silver L, Theuretzbacher U, Thomas J, Visi D. The small-molecule antibiotics pipeline: 2014–2018, Nature Reviews Drug Discovery 18, 739, 2019.
2. Singer AC, Kirchhelle C, Roberts AP. (Inter)nationalising the antibiotic research and development pipeline. The Lancet Infectious Diseases, 2019. https://doi.org/10.1016/S1473-3099(19)30552-3
3. O’Neill J. Review on Antimicrobial Resistance Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. London: Review on Antimicrobial Resistance; 2014. Available from: https://amr-review.org/sites/default/files/AMR%20Review%20Paper%20-%20Tackling%20a%20crisis%20for%20the%20health%20and%20wealth%20of%20nations_1.pdf Accessed October 11 2019
4. Mojzsis SJ, Arrhenius G, McKeegan KD, Harrison TM, Nutman AP, Friend CR. Evidence for life on Earth before 3,800 million years ago. Nature 1996; 384 (6604):55–59.
5. Curtis TP, Sloan WT. Exploring microbial diversity – a vast below. Science 2005; 309 (5739):1331–1333.
6. Melo MN, Ferre R, Castanho MA. Antimicrobial peptides: linking partition, activity and high membrane-bound concentrations. Nat Rev Microbiol 2009; 7 (3):245–250.
7. Kortright KE, Chan BK, Koff JL, Turner PE. Phage therapy: a renewed approach to combat antibiotic-resistant bacteria. Cell Host Microbe 2019; 25 (2):219–232.
Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.