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From Discovery to Resistance to Progress

At present time, the idea of germs being responsible for illness is far from novel. However, in the middle ages the pathophysiology of infection was unknown, and disease was attributed to causes like evil spirits, sinful behaviour and witchcraft to name a few.1

Louis Paster and Robert Koch are credited with coming up with the “germ theory of disease” which made popular the idea that a specific germ causes a specific disease. Meanwhile, Paul Ehrlich took this theory further by suggesting that we could create “magic bullets” to selectively target germs and pathogens. Possibly for the first time, the idea of being able to manage and cure infection was feasible.2

In 1928, Alexander Fleming famously and accidentally discovered penicillin from fungus; and by about 1945, penicillin was being administered to the masses. Needless to say, the management of infectious disease was revolutionized.2

Following the discovery of penicillin, several other classes were introduced to market during the “golden era” of antibiotics. For example:2

  • The macrolide prototype, erythromycin was introduced in 1952.
  • Lincomycin, the lincosamide prototype was introduced in 1962, although it has now been largely replaced by its synthetic derivative clindamycin.
  • Although introduced to market much earlier, vancomycin became a key player in the treatment of Methicillin resistant Staphylococcus Aureus (MRSA) in the 1970s.
  • Cephalosporin C, isolated from Cephalosporin acremonium, was never itself used as an antibiotic but eventually made way for the development of 4 generations of semi-synthetic cephalosporins that are still widely used.

As described above, we have come a long way in our understanding of infection as well as our development of antimicrobials. We have several classes of antibiotics at our disposal, giving us the ability to target a range of different organisms.

Despite this, we are facing significant challenges in the management of infectious disease. The cause of this is two fold. Firstly, resistance is becoming a widespread issue and secondly, there are few new antibiotics being introduced to the market.

Resistance occurs when organisms adapt upon exposure to antibiotics and are then able to evade destruction.3 For example, the reason beta lactam antibiotics are so effective is because the beta lactam ring prevents bacterial cell wall synthesis. Unfortunately there are several known methods of resistance to beta lactams. Some organisms have successfully modified the penicillin binding protein (PBP), which is the main target of beta lactam antibiotics. By doing so, they decrease the affinity of the antibiotic to its target, thus decreasing it’s efficacy. Other organisms produce beta lactamase, an enzyme that targets and hydrolyzes beta lactam antibiotics rendering them inactive.4

One of the biggest drivers of resistance is antibiotic overuse. In fact, studies have shown that there is a direct relationship between overuse and emergence of resistant strains. Other contributing factors include inappropriate prescribing and wide use of antibiotics in agricultural practices.5

Furthermore, although the 1950s-1970s was a lucrative period for the development of antibiotics, no new classes of antibiotics have been discovered since then. To add insult to injury, studies have revealed that approval of antibacterial agents decreased by 56% during 1998-2002 compared to 1983-1987.7 The reason for declining production and discovery of antibiotics is multifactorial, however ultimately the result is that clinicians now have fewer options at a time where infections are becoming more complex and resistance is becoming a global health issue.

The first reported case of multi-drug resistant gonorrhea is a frightening consequence of resistance with limited treatment options. An individual in the UK is confirmed to have contracted a strain of gonorrhea highly resistant to first line treatment with azithromycin (a macrolide) and ceftriaxone (a cephalosporin). Clinicians have now initiated treatment with intravenous Ertapenem, a powerful broad-spectrum antibiotic typically considered last line for severe infections.

As illustrated above, we are in desperate need of new antibiotics. As it turns out, our search for new therapeutic compounds may lie in the rich microbiome found in soil. Scientists at the Rockefeller University have discovered malacidins8, a calcium dependent class of antibiotics, via a meticulous soil screening process. Daptomycin is an example of a calcium dependent antibiotic currently available on the market. Malacidins have a 10 membered cyclic lipopeptide and contain a peptide core with 4 non-proteinogenic amino acids. A methylene on the branch at the terminus of the lipid tail is the only differentiating characteristic between the 2 malacidins (Malacidin A and Malacidin B) that have been isolated.

Interestingly, although malacidins lack the canonical Asp-X-Asp-Gly calcium-binding motif found in traditional calcium dependent antibiotics such as daptomycin, studies have shown that calcium binding is still a key aspect to their antibacterial activity and likely occurs via a different calcium binding motif.

Malacidins exhibit antimicrobial activity against a broad range of gram-positive bacteria including pathogens resistant to vancomycin, a powerful antibiotic usually reserved for serious infections. Impressively, researchers have so far been unable to induce resistance to malacidins under laboratory conditions; however, the possibility of horizontal gene transfer from bacteria in the environment is still a possibility.

Unfortunately, it is unlikely that we will see malacidins being prescribed to patients anytime soon. A drug must undergo a rigorous drug approval process before it can be deemed safe and effective for public use. Nonetheless, the discovery of malacidins is an exciting advancement and will hopefully make way for near future discovery of much needed broad-spectrum antibiotics, and agents that target gram-negative organisms.

Only time will tell, but it is possible that the solution to our current antibiotic crisis may be patiently waiting to be discovered in a soil sample.

References/Links:

  1. BBC: Medicine in the Middle Ages (accessed June 2018)
  2. White, R. (2012). The Early History of Antibiotic Discovery: Empiricism Ruled In Dougherty, T. J., Pucci, M. J. Springer (2012), Antibiotic Discovery and Development (3-32). New York, NY.)
  3. MedlinePlus: Antibiotic Resistance (accessed June 2018)
  4. BiologyDiscussion: Penicillins: Discovery and Structure (accessed June 2018)
  5. Ventola, C. L. The antibiotic resistance crisis: part 1: causes and threats. P. T. 2015 Apr;40(4):277-83.
  6. Rustam I. Aminov. A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future. Front Microbiol. 2010; 1: 134.
  7. Conly J., Johnston B. Where are all the new antibiotics? The new antibiotic paradox. Can J Infect Dis Med Microbiol. 2005 May;16(3):159-60.
  8. Los Angeles Times: In soil-dwelling bacteria, scientists find a new weapon to fight drug-resistant superbugs (accessed June 2018)
From Discovery to Resistance to Progress
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