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Discovery of new pathway explains high levels of antibiotic resistance in MRSA

Discovery of new pathway explains high levels of antibiotic resistance in MRSA

 


Understanding MRSA resistance: A new cell division pathway reveals how this dangerous pathogen evades antibiotics and advances the fight against superbugs.

Research: Two codependent pathways lead to high levels of MRSA. Image credit: Shutterstock AI / Shutterstock.com study: Two codependent pathways lead to high levels of MRSA. Image credit: Shutterstock AI / Shutterstock.com

MRSA and antibiotic resistance

The contribution of antibiotics to modern medicine cannot be underestimated. These have significantly reduced disease-related mortality and extended human lifespans to an unprecedented extent.

Unfortunately, the widespread and often irresponsible use of antibiotics has led to the proliferation of antibiotic-resistant bacteria that can survive even in antibiotic-rich environments due to antibiotic-mediated loss of non-resistant microbiota. The origin of “superbugs,” defined as pathogenic strains that are simultaneously resistant to multiple classes of antibiotics, raises significant public health concerns.

Methicillin resistance Staphylococcus aureus For example, (MRSA) consists of Gram-positive bacteria that can cause several potentially fatal respiratory infections. Conventionally, Staphylococcus aureus The infection was treated with β-lactam antibiotics.

Over time, this pathogen acquired resistance to β-lactamases, which led to the introduction of methicillin, a penicillin-like cytostatic antibiotic, as an alternative treatment. The increasing prevalence of MRSA has made methicillin treatment difficult, with current disease-related mortality rates ranging from 15% to 60%.

Previous observations have linked methicillin resistance in MRSA pathogens to methicillin resistance in exotic species. Mecha The gene encoding penicillin-binding protein 2a (PBP2a). However, the mechanism by which PBP2a protects previously methicillin-sensitive cells is Staphylococcus aureus (MSSA) The cause of β-lactam action remains unclear.

About research

In this study, multiple Staphylococcus aureus To elucidate the mechanisms involved in the ability to overcome methicillin inhibition of transpeptidase-derived cell division, we examine strains that differ in methicillin resistance.

Experimental procedures include incubation of wild-type (SH1000), low-resistant MRSA (SH1000). Mecha+), and highly resistant clinical MRSA (COL; SCCmec Type I) under various methicillin concentrations of zero, 25 μg/ml, and 50 μg/ml. High-resolution atomic force microscopy (AFM) was then used to elucidate the structural changes in peptidoglycan (PG) with different combinations of drug loading and resistance tested.

Mutagenesis techniques were then used to generate genetically unique isogenic genes. Staphylococcus aureus Strains with different combinations of PBP1, PBP2, PBP2a, and inducible elements. These experiments allowed the researchers to identify different cell division pathways under different methicillin concentrations and elucidate alternative cell division processes that may circumvent traditional beta-lactamase action.

Research results

The progression from methicillin wild-type to highly resistant MRSA was observed to occur in two steps. First, acquisition of PBP2a circumvents the essential transpeptidase activity of native PBP2. Next, mutation in rpoB The gene, a subunit of bacterial polymerase that enables nucleotide replication and cell division, prevents MRSA from requiring PBP1, thereby disabling the functional pathway of methicillin action.

These mutations are important when: rpoB and rpoC; However, they may also be found in related genes such as: relative, clpXP, GDPP, pde2, and Listen, H. Previous studies had identified these mutations, but their association remained unclear.

This study shows that these mutations increase MRSA resistance to >50 μg/ml by inducing a cell division pathway independent of PBP1 transpeptidase activity, thereby interfering with the ability of methicillin to suppress PBP1. It was classified as “enhancing factor mutation”.

PBP2a showed low binding affinity for methicillin or other β-lactam antibiotics. Although PBP2a cannot completely replace the need for natural PBP2 or PBP1, it may form dimers with these molecules to enhance their activity and prevent inactivation by antibiotics .

conclusion

The current study has identified chromosomal missense “enhancement factor” mutations that are involved in the regulation of uniformly high levels of cellular physiology. antibiotic resistance. These are distinct from previously known accessory genes that reduce antibiotic resistance. Taken together, these findings suggest that a combination of genetic and environmental factors contribute to the occurrence of high levels of MRSA strains.

Low-level antibiotic resistance is possible when bacteria acquire a non-naturally mutated form of the PBP2 gene, called PBP2a. This tolerance is achieved by reducing drug binding. efficacy and form dimers with natural PBP2 and PBP1, thereby enhancing their activity during antibiotic stress.

A small portion of the bacterial population may subsequently develop mutations in the enhancer. rpoB and similar replication-related genes. These mutations eliminate PBP1, which is required for cell division, allowing bacteria to grow even under high concentrations of antibiotics.

Once high concentrations of methicillin successfully eliminate wild-type and even less resistant MRSA strains, the surviving remaining strains with enhancer mutations rapidly establish themselves as the dominant strain. Staphylococcus aureus Tensions escalate and ultimately contribute to the global MRSA crisis.

Studying these processes in parallel can help us understand the fundamental mechanisms of the bacterial cell cycle and reveal ways to control antibiotic resistance. ”

Reference magazines:

  • Adeji Orulana, A.F., Wacnik, K., Lafage, L., Others. (2024). Two codependent pathways lead to high levels of MRSA. Science 386(6721). doi:10.1126/science.adn1369.

Sources

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2/ https://www.news-medical.net/news/20241103/New-pathway-discovery-explains-MRSAs-high-level-antibiotic-resistance.aspx

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