A handful of microbes have put global health at risk. These are the superbugs, considered by the World Health Organization (WHO) to be one of the top 10 threats to public health and responsible for 1.27 million deaths per year. The WHO specifically targets 15 microorganisms considered “highly dangerous” due to their resistance to the available arsenal of antibiotics and their ability to spread or transmit resistance to other bacteria. Sworn enemies include, for example, resistant Gram-negative bacteria, Salmonella, Shigella, Pseudomonas aeruginosa and the methicillin resistant Staphylococcus aureusamong others. Concerning the latter, a study published Thursday in the magazine Science looked into their antimicrobial evasion mechanisms and discovered that, to be highly resistant, these microbes adopt a dual defense.

Methicillin resistant Staphylococcus aureus (MRSA) alone causes approximately 120,000 deaths per year worldwide. It is a “serious global threat”, explains Simon Foster, researcher at the University of Sheffield (United Kingdom) and author of the study which reveals a new defense mechanism of this bacteria. Methicillin was the antibiotic traditionally used against this microbe, but due to the emergence of MRSA and the toxicity of the drug itself, Foster says, it was no longer used. The problem is that methicillin belongs to a larger family of antibiotics, the beta-lactams, and MRSA has become resistant to almost all of them. “MRSA can sometimes be treated with other antibiotics, such as linezolid or tetracycline. However, in cases of serious infections, such as bacteremia or endocarditis, daptomycin or vancomycin should be used. The problem is that resistance has developed against each of them,” explains the expert.

The scientific community long ago discovered that MRSA had a unique feature: It had acquired a gene that codes for a component called MecA, which helps form the bacteria’s cell walls so it can grow and divide. This genomic particularity makes it resistant, but researchers knew that this characteristic alone was not enough to be highly resistant. “It was also known that there are other small changes that occur in bacteria that allow for a large increase in the level of resistance,” Foster adds in an email response. Scientists believed that these small genetic changes, called “activators” in scientific jargon, made MecA work better.

However, explains the University of Sheffield researcher, his new discovery overturned initial hypotheses and revealed that these activators “are not linked to MecA activity, but are part of another mechanism necessary for resistance high level”. Specifically, the authors discovered that MRSA adopts an alternative mode of cell division in the presence of antimicrobials to ensure its survival. “Using the newly discovered mechanism, bacteria divide in a different way that does not require a key activity that is normally necessary for them to divide and multiply,” explains the researcher.

These two defense mechanisms are synergistic: “Both are necessary for high methicillin resistance. MecA should be resistant at a low level, about 10 times more than a susceptible strain, and potentiation should be resistant at a high level, about 1,000 times more than a susceptible strain. Potentiation alone does not make them resistant,” says Foster.

According to the authors, their discovery opens the door to new therapeutic strategies to combat antibiotic resistance. Foster argues that the discovery of this new, previously unknown division mechanism is important on two levels: “First, it has been demonstrated that these bacteria have the ability to divide in a previously unknown way, which highlights the mechanisms that support the life of this organism. Second, it shows that the development of resistance is more complex than we previously imagined and uses the newly discovered pathway, which has important ramifications for the development of new treatments to control MRSA. The scientist assures that there already exist compounds to which this resistant bacteria is vulnerable and that the activity of each of its two defense systems could be mapped. to find other new treatments.

A worrying pathogen

Bruno González-Zorn, director of the Antimicrobial Resistance Unit at the Complutense University of Madrid and advisor to the WHO in this area, emphasizes that MRSA is one of the pathogens “that cause the most mortality and the most concern at the hospital level” and any advance in the knowledge of the biology of resistance that it generates, like this research, is important: “It is an article of fundamental biology where it is described that MRSA acquires a gene that confers resistance. But one in 10,000 people manages to have very high resistance and, until now, it was not known what made them highly resistant, because this gene alone was insufficient. The new discovery will not have immediate clinical implications, but it opens the door to the design of molecules capable of inhibiting this high level of resistance,” reflects the microbiologist, who did not participate in this research.

María del Mar Tomás, microbiologist at the A Coruña University Hospital Complex and spokesperson for the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), shares a similar opinion: “It is extremely interesting. Much research has focused on classic resistance mechanisms, those that act on antibiotics, but this study focuses on tolerance and stress mechanisms in bacteria, which can also influence resistance. Tomás emphasizes that Foster’s research, in which she was not involved, finds “the perfect link” to explain the high resistance of MRSA to antibiotics: “It is a mechanism that combines the union of MecA with a mutation in activating genes linked to cell division: the bacteria develops in a different, abnormal and disordered way, but it manages to prevent the action of the antibiotic.

The research published in Science also raises new questions, Foster admits. For example, whether MRSA may have other hidden mechanisms for evading antibiotics: “Our discovery of this new mechanism using an alternative division strategy demonstrates how little we know. We are currently working to elucidate the basis of the alternative mode of division and how activators actually work to promote resistance. This allows us to discover a whole range of cellular capabilities that we can now explore. There is always more to discover and understand,” says the scientist.

Another question is whether these same defense pathways are replicated in other resistant bacteria. For now, Foster says, the enhancers are associated with resistance to other types of antibiotics and have been found in other bacteria. “We are working to determine whether there is a common thread between the bacteria and whether this mechanism is more common than we previously suggested,” he explains.

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