Antibiotic-resistant bacteria, popularly known as ‘superbugs’, are one of the major threats to global public health. These microorganisms have once evolved to counteract the efficacy of antibiotics – usually by abusive or improper use of these drugs, in the case of their use in the treatment of diseases, such as influenza, caused by Virus and not a bacterium – little more can be done than committing to the patient’s immune system’s ability to fight infection.
In addition, the number of ongoing studies to develop new antibiotics is negligible, so the future does not seem to be too hopeful.
Specifically, the study, published in the journal “Cell”, describes an antibiotic that is naturally produced by a bacterium and dubbed “pseudouridimycina”, has a novel mechanism of action capable of destroying a broad spectrum of both sensitive and resistant bacteria. The antibiotics available and to cure bacterial infections in animal models – mice.
As explained by Stefano Donadio, co-director of the research, “among other results, our work highlights the importance of natural products to provide new antibiotics. And it’s that microbes have been billions of years developing ‘chemical weapons’ to kill other microbes.”
The antibiotic pseudouridimycine acts by inhibiting bacterial RNA polymerase, that is, the enzyme responsible for synthesizing the RNA of the bacteria. However, to date there is another available antibiotic which, called ‘rifampicin’, also acts by inhibiting this bacterial enzyme.
So, should bacteria resistant to rifampicin be expected to be resistant to pseudouridimycine? Well, no, since both its mechanisms and enzyme binding sites are different. This is so when they are administered in combination they add their antibiotic effects.
It’s more, the rate of spontaneous resistance of pseudouridimycine is only one tenth of that of rifampicin; in other words, the probability that a bacterium develops resistance to pseudouridimycine as a result of a spontaneous mutation is 10 times lower than that observed with rifampicin.
Specifically, pseudouridimycine acts as an analogous nucleoside inhibitor in bacterial RNA polymerase. That is, it mimics chemical compounds which, like building blocks, are used by the enzyme to synthesize bacterial RNA. Thus, what the antibiotic does is bind to RNA polymerase in the place where the building blocks – a molecule called ‘nucleoside triphosphate’ (NTP) – would do. And since the NTP can no longer be bound, the enzyme does not have the raw material to construct the RNA.
And does not this new antibiotic, as it does with the bacterial enzyme, also inhibit human RNA polymerase? Well, no. Pseudouridimycine is the first nucleoside analogue to selectively inhibit bacterial RNA polymerase but not human RNA polymerases.
As Richard H. Ebright, co-director of research, indicates, “since the point of attachment of NTP to bacterial RNA polymerase has exactly the same structure and sequence as the point of attachment of NTP to human RNA polymerase, most of the researchers believed it impossible that an analogous nucleoside inhibitor could inhibit bacterial RNA polymerase without doing the same with human. However, the pseudouridimycine contains a side chain that remains outside the point of attachment of the NTP and touches an adjacent point present in bacterial but not human RNA polymerase. The result is that the antibiotic binds much more strongly to the bacterial enzyme than to the human enzyme.
It’s more; as the authors point out, the fact that pseudouridimycine acts as an analogous nucleoside inhibitor explains the low rate of spontaneous antibiotic resistance.
As Richard H. Ebright reports, “the new antibiotic interacts with essential residues at the point of attachment of NTP that can not be altered without losing the activity of RNA polymerase and thus the viability of the bacterium. The alterations at the point of attachment of the NTP that prevent the new antibiotic from joining also make bacterial activity impossible, so that the bacterium eventually dies before it develops resistance.
In definitive, pseudouridimycine appears as a very promising drug to combat the increasingly pressing problem of bacterial resistance.