Humanity’s Quest to Overcome Antibiotic Resistance as Antibiotic Pipeline Continues to Dry Up

Sir Alexander Fleming on the cover of Time Magazine source:http://www.kilmarnockacademy.co.uk/famousafleming.htm
Sir Alexander Fleming on the cover of Time Magazine
source:http://www.kilmarnockacademy.co.uk/famousafleming.htm

“It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them… There is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”
Sir Alexander Fleming, 1945, Nobel Prize in Medicine for discovery of Penicillin

In my recent blog post, I discussed the “superbug” catastrophe, which I believe is triggered by the misuse of antibiotics in the treatment of urinary tract infections.  This blog post serves as the second and subsequent part to my series stressing the race against time to overcome the growing antibiotic resistance.  It is worth noting that antibiotic/antimicrobial resistance is a growing global public health concern that jeopardizes our abilities to treat even the most common of infections.  Resistance rates are ascending at alarming rates in all parts of the world, the United States included, and will undoubtedly be the biggest challenge humanity will face in the 21st century.

Since the discovery of what could arguably be considered as one of mankind’s greatest advancement in modern medicine, antibiotics have transformed our approach in treating infectious disease and saved millions of lives.  The war with microbial is unceasing and as of late, they are winning.  In 2013 alone, more than 2 million people are sickened by resistant infections, resulting in more than 23,000 deaths1. The WHO (World Health Organization) admits that the “antibiotic pipeline is drying up while resistance to existing drugs is increasing”2.  Putting things into perspective, since the day I was born (1988), not one single new class of antibiotic have been discovered.  The only efforts are modifications and improvements made to the already existing antibiotics.  In my opinion, the lack of effort boils down to two barriers.

Scientific Barrier

The development process of antibiotics parallel that of mobile phone applications (something I am somewhat familiar with).  In both universe, virtually all the traditional concepts have been developed, ultimately leaving consumers with inferior products.  We cannot deny that the rate of resistance is accumulating faster than the current rate of discovery.  In the last decade, we (U.S FDA) have only approved 11 new antibiotics while microbial have developed numerous more clever, sophisticated ways to resist drugs in approximately 2 million Americans each year.

the use of iChips to isolate and cultivate new microbes source: http://www.popsci.com/ichip-new-way-find-antibiotics-and-other-key-drugs
the use of iChips to isolate and cultivate new microbes
source: http://www.popsci.com/ichip-new-way-find-antibiotics-and-other-key-drugs

Rather than spending resources on modifying already existing antibiotics, scientists essentially need to shift their focus onto developing new antibiotics at a swifter pace.  We have only cultured merely 1% of our planet’s bacteria; so theoretically, numerous innovative process are still waiting to be discovered to cultivate the previously unculturable bacteria.   A good example of this is the recently developed “game changing” antibiotic class coined as Teixobactin.  This small molecule antibiotic is cultivated using developed by scientists at Northerneastern University using iChip, “a miniaturized version of the original chamber that allows isolation and cultivation of new microbes in a single step”6.   Teixobactin has demonstrated effectiveness against Staphylococcus arueus, Methicillin-resistant Staphylococcus arueus (MRSA), Mycobacterium tuberculosiss, C. difficille, Bacillus anthracis, and Vancomycin-resistant enterococci (VRE) in the labs without detectable resistance.  It inhibits cell wall synthesis by binding to motif of lipid II (similar to vancomycin) and lipid III, precursors of peptidoglycan and cell wall teichoic acid, respectively.  Resistance risks reduction is owed to Teixobactin’s ability to binding to less mutable fatty molecules (more specifically, the undecaprenyl-PP-sugar region of the peptidoglycan precursors)3.  Unlike previous classes of antibiotics, Teixobactin does not bind to mutable genes in bacterial proteins.  Nevertheless, the drug is only in its initial stages, with aims for human trials later this year.   Although Teixobactin offers exciting possibilities and opens many unopened doors in the world of antibiotics, it is not expected to hit market for another 4-5 years.

Economic Barrier: A Poor Return on Investment

As scientists continue to seek new weapons to wage ongoing war against microbial, pharmaceutical companies suffer financially.   Recently, Forbes published an article stating that the cost of developing a single antibiotic–from R&D to marketing– could be as high as $5 billion!4  Much of this is attributed to astronomical probabilities (up to 95%) of the antibiotics failing during their development stages and the extensivity of FDA’s approval process.  It is much more profitable for pharmaceutical companies to finance drugs with indications for treatments of chronic disease states such as diabetes, asthma, hypertension, and depression.  Doing so, they can enjoy fat returns on their investments and appreciates the minimal drug resistance risks.  For example, Pfizer, the decorate company that discovered penicillin during WWII, turned a blind eye on antibiotics.  Instead, the company poured their heart and soul into developing “money makers” such as Viagra, Lipitor, Celebrex, Zoloft, and Effexor.

In 2012, President Obama signed the Generating Antibiotic Incentives Now (GAIN) Act into law as an effort to revive our nation’s leadership in antibiotic development.  It provides incentives for pharmaceuticals companies by extending drug patents of antibiotics designed under Act for an additional five years.  Furthermore, the drugs under the law’s supervision are prioritized for fast-track FDA approval, thus speeding up the development process’ timeline.  Drug development under the GAIN Act also requires the FDA to provide the clinical trial guidance to aid manufactures, proving them with a clear pathway to developing pathogen-focused antibiotics.5

Below are common pathogens that are in trending in resistance that we should be concerned about, and a comparison/analysis chart of the most recently approved antibiotics for the treatment of MDR gram positive and gram negatives bacteria.   Furthermore, included are some of the newer antibiotics in the pipeline designed to conquer MRSA, VRE, and MDRSP.  Please let me know if you have any questions or suggestions.  The next part of my ongoing series will explore the different options to preserve antibiotics, promote public awareness,  and address the need for concerted actions.

Gram-positive pathogens such as

  • Streptococcus pneumonia
    • well known for causing pneumonia, ear infections, bloodstream infections and meningitis;
  • Staphylococcus aureus
    • Culprit for majority of skin and bone infections
  • Enterococci
    • responsible for hospital-acquired infections

Gram-negative pathogens such as

  • Escherichia coli
    • Culprit in the recent chipotle outbreak that lead to nearly 40 hospitalizations
    • Famous for ordinary infections such as urinary tract infections, as well as gastroenteritis, septicemia, and pneumonia
  • Salmonella and Escherichia coli
    • foodborne infections
  • Acinetobacter baumanniiPseudomonas aeruginosa and Klebsiella spp.
    • accountable for infections transmitted in healthcare settings.
newer antibiotics in the pipeline designed to conquer MRSA, VRE, and MDRSP
newer antibiotics in the pipeline designed to conquer MRSA, VRE, and MDRSP
comparing the most recently approved antibiotics for the treatment of MDR gram-positive bacteria
comparing the most recently approved antibiotics for the treatment of MDR gram-positive bacteria
comparing the most recently approved antibiotics for the treatment of MDR gram-negative bacteria
comparing the most recently approved antibiotics for the treatment of MDR gram-negative bacteria

Reference

  1. Bulletin of the World Health Organization 2011;89:88–89. doi:10.2471/BLT.11.030211
  2. http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf
  3. http://www.nature.com/nature/journal/v517/n7535/full/nature14098.html
  4. http://www.forbes.com/sites/matthewherper/2013/08/11/how-the-staggering-cost-of-inventing-new-drugs-is-shaping-the-future-of-medicine/
  5. http://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2013/11/07/gain-how-a-new-law-is-stimulating-the-development-of-antibiotics
  6. http://www.novobiotic.com/compounds-publications/
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