Neutrophil_MRSA_II

Human neutrophil ingesting MRSA. Credit: National Institute of Allergy and Infectious Diseases (NIAID)

Antibiotics have been the cornerstone of modern medicine since Fleming first discovered Penicillin. They have reduced childhood mortality and increased life expediencies across the globe. However, the drastic increase in the number of infections caused by multi-drug resistant bacteria, heralds a new era of antimicrobial drug discovery.

Researchers from The Scripps Research Institute in California have made a giant leap forward in the race to find antibiotics that are effective against antibiotic-resistance.

What is antibiotic resistance? 

Bacteria are master escape artists. They are extremely good at adapting themselves to avoid being killed. Microbial resistance is a natural process but it has been accelerated in recent years by the inappropriate use of antibiotics. Bacteria predominantly use three strategies to evade destruction: 1) preventing entry of the drug into the bacterium, 2) modifying the molecule which the drug targets (often on the cell wall) and 3) directly inactivating the drug [1].  Pretty impressive for a single cell organism!

The first cases of methicillin-resistant Staphylococcus aureus (MRSA) were reported in the United Kingdom and the United States in 1962 and 1968 respectively [2]. Since then, the problem has become so prevalent that The Centre for Disease Control (CDC) estimates that 2 million people are newly infected with antibiotic-resistant bacteria each year in the United States and 23,000 of them will die as a direct result of these infections [2].

Antibiotic resistance is not only a public health concern but it is also a public financial concern. For example, the CDC estimates that $3,800,000,000 could be saved by the United States health service over 5 years, if an effective treatment for infections caused by antimicrobial resistant Clostridium difficile (C. difficile) were available [2].

New research may have the answer

A breakthrough study by Okano et al, published in the journal Proceedings of the National Academy of Sciences, has focused on the antibiotic vancomycin, which is part of a class of antibiotics that in the past has been relatively successful at avoiding bacterial resistance [4].

However, even the most successful drug candidates struggle against the evolution of bacterial defenses. Vancomycin resistance was first detected in 1987 in vancomycin-resistant enterococci (VRE). VRE are a species of bacteria which are associated with blood, urinary and wound infections and are ranked fourth on the WHO’s list of bacteria which pose the greatest risk to human health [3].

In this new study, researchers modified vancomycin’s structure and essentially supercharged it against VRE. This new and improved vancomycin or [Ψ[CH2NH]Tpg4]vancomycin, not only displayed an increased effectiveness at killing VRE, but it also prevented the bacteria from developing resistance to the antibiotic [4].

The investigators established that the supercharged vancomycin was so successful because it had three independent mechanisms of killing the bacteria. This made it extremely difficult for the microorganism to adapt and become resistant [4].

Therefore, this work has not only produced a new and improved antibiotic, but it has also created a potential prototype for a new class of antimicrobials, which uses a multi-modal approach to combat bacterial resistance.

As always, it is important to point out is that it is still early days for this candidate, as it needs to be tested in both animals and humans. However, as we are on the threshold of a “post-antibiotic era” this is an exciting and very necessary advancement in the fight against superbug infections.

 

References:

[1] Blair JMA, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJV. (2015). Molecular mechanisms of antibiotic resistance. Nature Reviews Microbiology 13, 42–51.

[2] Centers for Disease Control and Prevention, https://www.cdc.gov/drugresistance/index.html

[3] WHO list of antimicrobial resistant bacteria

[4] Okano AB, Isleya NA and Bogera DL. (2017). Peripheral modifications of [Ψ[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1704125114