The picture shows a modified version of the antibiotic Vancomycin from a paper in Proceedings of the National Academy of Sciences of the United States of America (PNAS… unfortunate acronym!). The authors Okano et al have “manufactured” this new version of Vancomycin to have potent activity against normally Vancomycin-resistant bacteria.
Vancomycin, and the other common glycopeptide Teicoplanin, are two of the most commonly used antibiotics in hospital medicine. They are active against almost all Gram-positive bacteria including Staphylococcus spp., Streptococcus spp. and Enterococcus spp. to name just a few. They are often used first-line to treat infections with resistant bacteria such as Meticillin Resistant Staphylococcus aureus, Penicillin-resistant Streptococcus pneumoniae and Enterococcus faecium. More importantly they are usually part of the second-line treatment of many infections in patients with beta-lactam allergies e.g. intraabdominal sepsis where the first choice is Amoxicillin PLUS Gentamicin PLUS Metronidazole and the second choice is Vancomycin PLUS Gentamicin PLUS Metronidazole or in severe pneumonia where first choice might be Amoxicillin PLUS Clarithromycin and the second choice is Vancomycin PLUS Levofloxacin.
Losing this class of antibiotics due to resistance would cause major problems in the routine management of patients and a failure of many empirical antibiotic treatment regimens.
What is Vancomycin and how does resistance occur?
Vancomycin is a glycopeptide antibiotic whose bactericidal mechanism of action involves binding to the d-ala-d-ala tail of peptidoglycan in order to block cross-linkage of peptidoglycans, thereby preventing bacterial cell wall formation. (The peptidoglycan is a mesh-like layer, consisting of sugars and amino acids, forming the cell wall).
The glycopeptide antibiotics are derived from naturally occurring soil bacteria: Amycolatopsis orientalis produces Vancomycin and Actinoplanes teichomyceticus produces Teicoplanin. It makes sense that these bacteria are able to protect themselves from the antibiotics they produce; they do this by switching on genes known as Van genes (commonly known genes are VanA and VanB). These genes change the make-up of the cell wall which in turn prevents the glycopeptides binding and causing the bacterium self-harm.
The Van genes can be on mobile genetic elements within the bacteria, known as transposons. These transposons (see website for more about antibiotic resistance and these genetic elements) can then cross into different species of bacteria, which is what is thought to have occurred with Glycopeptide Resistant Enterococcus (GRE); the Enterococcus spp. has acquired either VanA or VanB. The VanA and VanB genes encode a different tail to the to the d-ala-d-ala tail of peptidoglycan, containing d-ala-d-lac, which means that the glycopeptide antibiotics can’t bind and so their antimicrobial activity or effectiveness drops a 1000 fold.
Worryingly, the VanA and VanB genes can also cross into Staphylococcus aureus creating Glycopeptide Resistant Staphylococcus aureus (GRSA). This mutation creates a serious human pathogen which is very difficult to treat (see previous blog for more information).
It took time for this resistance to glycopeptides to make it into human pathogens. Vancomycin was introduced in 1958, GRE was discovered in 1987 and GRSA in 2002… but it did happen and GRE especially is now part of everyday microbiology in the UK. Antibiotic resistance is a problem whether we like it or not! But maybe our saviour is here… and this is where the paper in PNAS comes in.
The authors of the PNAS paper have found a way of modifying the old-fashioned Vancomycin to restore its ability to bind to the d-ala-d-lac peptidoglycan. They have done this by fiddling with the pocket of the Vancomycin molecule that binds to the peptidoglycan allowing the new molecule to bind to both d-ala-d-ala and also d-ala-d-lac. The new molecule is active against bacteria with either normal or genetically modified peptidoglycan.
Having reversed the Van gene mediated resistance the authors then went on to make 2 further modifications of the Vancomycin molecule away from the binding pocket which has led to new mechanisms of action, independent of the normal binding process of Vancomycin. The first modification inhibits an enzyme involved in cell wall synthesis independent of the need to bind to d-ala-d-ala. The second modification induced bacterial cell wall permeability and thereby caused bacterial cell death. The new antibiotic has 3 distinct mechanisms of action which act synergistically, hence creating a potent antimicrobial. This new antibiotic has an MIC to GRE of 0.01-0.005 mg/L compared to the normal Enterococcus spp. Vancomycin MIC of 1-2 mg/L… i.e. it is 100-400 times more active!
Can resistance to the new version of Vancomycin occur?
The authors tried to produce Enterococcus spp. resistant to their new Vancomycin molecule in vitro but were unable to do so. In order for a bacterium to become resistant to an antibiotic with 3 independent mechanisms of action, the bacterium would have to acquire resistance to ALL 3 mechanisms simultaneously before one of the mechanisms managed to kill the bacterium! This is very unlikely. This is a similar principal to that already used by Microbiologists when they combine different classes of antibiotics to treat infections in the expectation that a bacterium is unlikely to become resistant to all of the antibiotics at the same time, see us Microbiologists do know what we’re doing…it’s not just indecisiveness or triple the choice and hope!
It is unclear how the VanC type of resistance fits in to all of this and the authors don’t comment on it. VanC is inherent to Enterococcus casseliflavus and Enterococcus gallinarum. VanC has a different type of peptidoglycan tail with d-ala-d-ser and this may or may not be a binding site for this new version of Vancomycin. In reality this doesn’t really matter because the 2 other mechanisms of action of this new antibiotic will bypass the VanC resistance mechanism and so the bacteria should remain sensitive.
What might be the drawbacks to this new antibiotic?
The authors looked for any potential toxicity using in vitro experiments, mixing the new molecule with different types of human cells, and could find nothing of concern. HOWEVER this does not mean that this new compound will be safe in humans. There will need to be an awful lot more work done before any compound like this enters clinical trials. There is an old saying in medicine that “the most potent medicines often have the most potent side-effects…” so we’ll have to wait and see.
This new “designer antibiotic”, created in a laboratory, represents a potentially exciting development in the battle against antibiotic resistance.
This new antibiotic with its multiple mechanisms of action creates potent activity against the target bacteria and makes the evolution of antibiotic resistance very unlikely; this would be a real benefit in the future treatment of Gram-positive infections.
Time will tell if this antibiotic will ever make it to a pharmacy near you, but if other antibiotics can be created in this way the future may not be as bleak as we once thought…. although there is still no new antibiotic against Gram-negative bacteria! Gram-negative bacteria are the ones that keep Microbiologists awake at night… they are the ones we have no new approaches for and they kill humans… come on researchers I challenge you… make me a new Gram-negative antibiotic. That will make me really excited!!!
Peripheral modifications of vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics. Okano A, Isley N, Boger D, PNAS 30 May 2017 published ahead of print