A brief history
Even though Alexander Fleming discovered the first antibiotic penicillin in 1928, it was introduced into the market as a commercial therapeutic for bacterial infection, only in 1940. It was Gerhard Domaghk who developed the first commercial antibacterial Prontosil, a sulfonamide, in 1930s.
The introduction of penicillin marked the beginning of the ‘Golden Era’ for antibiotic discovery. For the next 40 years, many antibiotic classes e.g. β-lactams, aminoglycosides, tetracyclines, macrolides, glycopeptides and fluoroquinolones, were discovered and developed. Each class typically contains several antibiotics that are either novel or modified versions of previous types (e.g. penicillin and cephalosporin are members of the β-lactam class).
Starting from 1987, there was a discovery void for the next ~30 years (discovery of a new class of antibiotic – Lipopeptide – Daptomycin) and it lasted till 2015, when scientists discovered Teixobactin (novel class of peptidoglycan synthesis inhibitor), the first medication capable of destroying ‘drug resistant’ bacteria
Superbugs – The Challenger to Antibiotics
“Superbugs” is a term used to describe strains of bacteria that are resistant to most of the antibiotics used today.
Antibiotic resistance is a naturally occurring phenomenon in which bacteria gradually develops resistance to antibiotics. This occurs due to changes or mutations in the bacterial DNA or the acquisition of antibiotic resistance genes from other bacterial species through horizontal gene transfer. These changes enable the bacteria to survive the effects of antibiotics designed to kill them.
Antibiotic resistance is growing at an alarming pace around the world. According to WHO, antibiotic resistance is one of the biggest threats to health worldwide. 700,000 people die from bacterial infections every year and the annual mortality due to antimicrobial resistant infections is estimated to reach 10 Million by 20506. The global economic cost of such a rise in infection related mortality and morbidity is estimated to be $100 trillion.
The major cause for this resistance seems to be the inappropriate use or overuse of antibiotics. For example, there are many countries where antibiotics are available without a prescription and are often wrongly used to treat infections such as coughs and colds, which are caused by viruses, not bacteria. Unnecessary exposure to antibiotics creates a fertile ground for the bacteria to develop resistance.
How do we overcome resistance?
Nearly all the antibacterial drug classes being used today were discovered during the Golden Age of antibiotic innovation between 1940 and 1987). These drugs are gradually losing their effectiveness in treating the drug resistant bacteria.
The slumping performance of these drugs is stimulating new treatment innovations. Here are a few examples of innovations in antibiotics:
CRISPR-Phage (crPhage) platform1,3: It is a breakthrough innovation in antibacterial therapies, based on a gene editing system called as CRISPR-Cas3.
CRISPR is a group of DNA sequences found in bacteria that act as a defense system against viruses that could infect a bacterium. CRISPRs are a genetic code that is broken up by “spacers” of sequences from viruses that have attacked a bacterium. If the bacteria encounter the virus again, a CRISPR acts as a sort of memory bank, making it easier to defend the cell.
Cas3 is the CRISPR-associated protein is an exonuclease that essentially shreds a targeted DNA. The platform combines the antibacterial power of CRISPR-Cas3 with an efficient, safe delivery vehicle called as bacteriophage to find and destroy specific bacteria selectively, such as herpes simplex, hepatitis B, and Epstein-Barr.
SATIN platform2: The Selective Antibiotic Target identificatioN platform identifies new molecular targets in the bacteria to disrupt their growth, viability and resistance mechanisms. High throughput next generation sequencing, advanced bioinformatics and machine learning are used to continuously analyze bacterial transposon libraries, allowing the researchers to track bacterial events throughout drug development. This facilitates the development of more targeted antibiotics for specific pathogens, which in turn, reduces the spread of antibiotic resistance.
This platform is developed by a UK based biotech company Discuva (Now acquired by Summit therapeutics). In 2014, Roche entered into a partnership with Discuva to develop new class of antibiotics for the treatment of multidrug-resistant bacteria using the SATIN technology platform.
iChip Technology4: Developed by Northeastern university, this platform enables the researchers to tap into a wide variety of microorganisms that normally won’t grow under the artificial conditions of the lab. For example, 99% of soil-based microorganisms won’t grow in a petri-dish. The iChip isolates and grows individual microorganisms in their natural soil, each in its own small chamber.
The device works by sorting individual bacterial cells harvested from soil into single chambers. The device is then buried back in the ground. Chemical nutrients in that environment diffuse into the iChip, allowing the bacteria to thrive in a more natural setting than a petri-dish. iChip expands the fraction of in-vitro growable micro-organisms to 50%.
Using this device, Teixobactin was discovered from an unknown gram-negative bacterium found in soil. Teixobactin is the first commercially viable member of a novel class of peptidoglycan synthesis inhibitors, developed in the last three decades. It kills bacteria without detectable resistance including superbugs such as MRSA.
There is an urgent need to tackle antimicrobial resistance as the existing drugs are losing their efficacy. Several national and international incentive programs such as CARB-X, BARDA and ND4BB have been initiated to accelerate innovation in antibiotic8. However, the innovations have not kept pace with which infections and resistance are developing. As per WHO5, there are a total of 48 antibiotics in development targeting WHO priority pathogens (Mycobacterium tuberculosis and Clostridium difficile). However, only five of these meet one of the four criteria that WHO uses to define a drug as “innovative”. Given the grim prognosis of morbidity and mortality associated with drug resistant infections in the coming three decades, one cannot help but wonder if there´s still hope for finding breakthrough medicines or if it is too little too late.
CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats
SATIN: Selective Antibiotic Target Identification
iCHIP: Isolation Chip
CARB-X: Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator
BARDA: Biomedical Advanced Research and Development Authority’s
ND4BB: New Drugs for Bad Bugs
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