To allow the treatment of bacteria with resistances to, for example, β-lactams, there is a need for a variety of antibiotic medicines with different structures and modes of action.
One common alternative to penicillins is a non-β-lactam antibiotic called vancomycin (Vancocin), which was originally approved for use in 1958. After its initial introduction it was superseded by the β-lactams that provided a cheaper and less toxic alternative to treat antibiotic infections. Over time, however, interest in vancomycin has resurged and it is now one of the most common non-β-lactam antibiotics in use.
Vancomycin has a very complicated structure, which contains carbohydrate groups, a number of substituted benzenes and various amide (or peptide) bonds. It has a molecular weight far above that of penicillins and most β-lactam antibiotics. As it does not contain a β-lactam ring, we can assume that it kills bacteria in a different way to β-lactam penicillins.
In fact, vancomycin targets the precursor molecules that form peptidoglycan directly.
Vancomycin binds to branching amino acid chains that make up some of the individual peptidoglycan strands. These amino acids are designed to cross-link with other amino acids, using an enzyme called peptidoglycan synthetase, in order to form strong cell walls made of many layers of interlinked peptidoglycan chains. Vancomycin acts by binding to the branching amino acids and preventing the synthetase enzyme from interacting with them. So, the regeneration and construction of peptidoglycan cell walls is unable to take place and over time the protective cell wall surrounding the bacterial cell breaks down.
Resistance to vancomycin is known and relies on altering the structure of the final amino acid at the end of the peptidoglycan chain that undergoes cross-linking. Vancomycin no longer has a complimentary shape to this new structure of amino acids and therefore cannot bind and inhibit the action of the peptidoglycan synthetase enzyme – which is also modified in order to accept the new amino acid structure. Bacteria that make their cell walls using this modified peptidoglycan precursor are therefore resistant to vancomycin and their peptidoglycan synthetase enzymes successfully bind to the amino acid sites.
An alternative antibiotic is daptomycin (Cubicin), approved for use in 2003. Daptomycin has yet another mechanism of action which revolves around its molecular structure. The ring of amide bonds provides a hydrophilic polar head and the liphophilic alkyl chain represents the non-polar end of the molecule. Daptomycin is mainly effective against gram-positive bacteria as it can diffuse through the surrounding peptidoglycan layers. Once it reaches the cell membrane its lipophilic ‘tail’ inserts into the phospholipid membrane of the cell.
This ‘tail’ allows for daptomycin to integrate itself into the phospholipid bi-layer of the bacterial cell membrane as both the ‘tail’ and the phospholipid fatty acid chains are lipophilic. Once many daptomycin molecules integrate themselves into the cell membrane they begin to stretch and contort it, producing holes from which ions within the cell can leak out. Once ion leakage occurs lost ions cannot be easily replaced by the bacterium; the cell loses its ability to replicate and produce proteins essential for its survival.
Daptomycin has catalogued cases of resistance, however, these are rare and the mechanism through which resistance occurs is currently unknown. As such daptomycin looks to be a valuable alternative where vancomycin resistant bacteria have developed. Thus far, clinical trials have shown equal or greater effectiveness than vancomycin in combating bacterial infections.
More importantly, studies suggest that vancomycin has a damaging effect on the kidneys through prolonged use. However, daptomycin has shown none of these toxic side effects and in some circumstances it has helped to alleviate similar kidney damage. Therefore, daptomycin could not only be a more effective form of treatment but also a safer one.
This potent antibiotic is steadily gaining popularity and in 2015 of the 6075 patients catalogued in the Cubicin Outcomes Registry and Experience database (CORE) there was an 85% success rate in treatment to those prescribed daptomycin. The CORE database was set up specifically to catalogue uses of daptomycin in a clinical setting and analyse the results. Overall these appear to be promising with less than 5% of patients reporting adverse effects from the treatment.
With further trials and study, these statistics can only improve as more effective analogues and combinations with other prescriptions are used.
At the start of 2017, a team of chemists and biologists at York reported new antibiotics of potential use for the treatment of gonorrhoea. They harnessed the therapeutic effects of carbon monoxide-releasing molecules – these molecules bind to the bacteria that causes gonorrhoea, preventing the bacteria from producing energy and killing it.
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