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Why We Need Better Antibiotics and What Biotech and Pharma Are Doing About It

Written by: Zach Stamp
Date: 09 October 2018

Antibiotics extended the human lifespan — but now they’re under threat.  Breaking news from three companies this month showcase how big pharma is stepping up to the plate.

The average human lifespan has more than doubled since 1900 and this trend is expected to continue. But the biggest leaps in medical history have predominantly been due to advances in infectious disease, such as antibiotics, public sanitation, and immunization.

Recently these achievements have been under threat from the rising tide of antibiotic resistance.  Fortunately, recent advances from Merck, Genentech, and Nosopharm are addressing this problem.  Let’s examine why and how...

The problem with antibiotics

Doomsdayers and countless Hollywood B-movie directors are fond of referencing the “antibiotic apocalypse”.  While most people might think this is a trope, historians, microbiologists, doctors, and public health officials all take this possibility quite seriously.  

According to a 2009 Science publication ominously titled “Looming Global-Scale Failures and Missing Institutions” microbial resistance is one of several:

serious, intertwined global-scale challenges spawned by the accelerating scale of human activities” that is “outpacing the development of institutions to deal with them and their many interactive effects”.  

England’s Chief Medical Officer Prof Dame Sally Davies more succinctly referenced antibiotic resistance as “the end of modern medicine”.

The truth is, microbes have always been a significant threat. The 1918 Spanish flu pandemic killed between 20-40 million people — more than died in WWII.  More recently, the 2009 swine flu (H1N1) pandemic rapidly grew to laboratory-confirmed cases in 214 countries — with 18 thousand deaths.

The term “antimicrobial resistance” refers to previously susceptible microbes such as bacteria, viruses, and fungi becoming immune to the effects of antibiotics.  Although most pandemics are viral, gram-negative bacteria are much more routine and costly problem.

Most of us haven’t lived without antibiotics so we don’t remember what it was like without them.  According to a 2011 article in the New England Journal of Medicine, gram-negative bacteria accounted for more than 30% of hospital-acquired infections (which caused almost 99,000 deaths in 2002 alone).  This could reduce the global gross domestic product by an estimated $100 trillion by 2050. We may see increased deaths from minor injuries, cuts, and surgical procedures over the next few decades.

The problem with antibiotic use

So why are we losing this battle? It’s a simple equation, we’ve been overusing antibiotics, and nature loves a balance, so microbial resistance is on the rise.

Microbes are a worthy enemy with several evolutionary advantages that predispose them to fight off antibiotics. They can mutate rapidly and/or transfer resistance genes between species.  This is basic biology, microtia out-compete each other so antibiotic resistance occurs as naturally as the antibiotics we originally sourced from mold.

Genetic mutation is estimated to be a random occurrence one microbe out of 1-10 million.  However, there are lots of bacteria. A single bacterial cell can form a colony of >1 million cells in under 10 hours, and antibiotic use selects for the survival of resistant organisms.

According to the WHO Fact Sheet on Microbial Resistance, 490k people developed multi-drug resistant TB globally in 2016 alone.  The US Department of Labor reports that common organisms that have developed resistance to multiple antibiotics (known as multidrug-resistant organisms or MDRO) including:

  • methicillin/oxacillin-resistant Staphylococcus aureus (MRSA)
  • vancomycin-resistant enterococci (VRE)
  • extended-spectrum beta-lactamases (resistant to cephalosporins and monobactams)
  • penicillin-resistant Streptococcus pneumoniae (PRSP)
  • multi-drug resistant tuberculosis (MDR-TB)

But even more worrisome, we are running out of alternatives. A 2011 review summarizes the difficulties. While 20 antibiotic classes were marketed between 1940-1962, only 2 have made it to clinical trials between 1962-2011, both of which are in Phase 1 trials (and therefore statistically unlikely to reach the market).  

To summarize,  not enough analogs have been reaching the market to combat antibiotic resistance — particularly those active against gram-negative bacteria.

 What biotech & pharma are doing about the challenge

 When natural compounds are lacking companies must resort to engineering antibiotics which is an expensive process, producing expensive compounds, with a low profit-margin.

 However recently biotech and pharma have announced several novel solutions to the antibiotic crisis:

  • Artificial Intelligence: Scientists have developed machine-learning algorithms to screen peptide sequences of novel compounds for antimicrobial activity. This could increase the efficiency of early-stage drug development efforts.
  • Gene editing: The human genome was sequenced in 2003, now the emerging discipline of precision medicine is using genes and gene-editing to target therapies. In Sep 2018, scientists at the University of Colorado reported in Science that they had successfully used CRISPR gene editing to disrupt resistance in an Escherichia coli species.
  • Natural compounds: In April 2018, researchers from the University of Chicago and the biotech company Nosopharm isolated a novel class of antibiotics from a unique community —odilorhabdins or ODLs a “symbiotic bacteria found in soil-dwelling nematode worms that colonize insects for food”. This is exciting because it’s not only a novel antibiotic, it’s a novel mechanism of action.
  • Chemical optimization: In September 2018, Genentech reported the release of a new class of antibiotics developed in concert with RQx Pharmaceuticals which is active against gram-negative bacteria.  Their paper, released in Nature the same month reports on the five-year project to chemically optimize arylomycins,  (natural compounds with weak activity and limited spectrum) into the G0775 molecule, a “potent, broad-spectrum activity against Gram-negative bacteria
  • Novel applications: Not to be outdone, Merk announced in Sep 2018 that it would file a supplemental new drug approval to use Zerbaxa, a cephalosporin composed of ceftolozane and tazobactam in either ventilated hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). The drug was already FDA-approved in 2014 for complicated intrabdominal and urinary tract infections.

Conclusion

While Genentech’s success is exciting and revolutionary, it has only been proven in test-tubes and mice. In contrast, a drug like Zerbaxa is an incremental improvement, with strong phase III clinical evidence and pre-existing FDA-approval.  

But is this important? Successes in this field were sorely needed and there is room for all of the advances in our list to have a tremendous impact.  

Here at EPM Scientific, we like to think holistically.  We ensure the best talent is in the right place at the right time to ensure good medicine is available to patients in need. Which is a good approach because we’re all in this together! Maybe the right response to a “serious, intertwined global-scale challenge” is a positive intertwined global-scale solution!