Abstract
The three fundamental mechanisms of antimicrobial resistance are (1) enzymatic degradation of antibacterial drugs, (2) alteration of bacterial proteins that are antimicrobial targets, and (3) changes in membrane permeability to antibiotics. Antibiotic resistance can be either plasmid mediated or maintained on the bacterial chromosome. The most important mechanism of resistance to the penicillins and cephalosporins is antibiotic hydrolysis mediated by the bacterial enzyme beta-lactamase. The expression of chromosomal beta-lactamase can either be induced or stably depressed by exposure to beta-lactam drugs. Methods to overcome resistance to beta-lactam antibiotics include the development of new antibiotics that are stable to beta-lactamase attack and the coadministration of beta-lactamase inhibitors with beta-lactam drugs. Resistance to methicillin, which is stable to gram-positive beta-lactamase, occurs through the alteration of an antibiotic target protein, penicillin-binding protein 2. Production of antibiotic-modifying enzymes and synthesis of antibiotic-insensitive bacterial targets are the primary resistance mechanisms for the other classes of antibiotics, including trimethoprim, the sulfonamides, the aminoglycosides, chloramphenicol, and the quinolone drugs. Reduced antibiotic penetration is also a resistance mechanism for several classes of antibiotics, including the beta-lactam drugs, the aminoglycosides, chloramphenicol, and the quinolones.
Researchers have discovered a significant and previously unknown mechanism that many bacteria use to resist antibiotics.
Using a combination of computation and physical observation in the laboratory, the researchers have unraveled a sophisticated process that some commonly occurring bacteria use to save themselves from the rifamycin class of antibiotics which occur naturally and are also manufactured to treat infectous disease.
What mechanisms do bacteria use to resist antibiotics?
The three fundamental mechanisms of antimicrobial resistance are (1) enzymatic degradation of antibacterial drugs, (2) alteration of bacterial proteins that are antimicrobial targets, and (3) changes in membrane permeability to antibiotics.
Rifamycins work by binding to Ribonucleic Acid (RNA) polymerase, a protein essential for bacterial life.
The resistance bacteruia which occur widely in the environment and in some human pathogens, have developed a protein that can eject the antibiotic from RNA polymerase. Once the rifamycin is dislodged, they use specially adapted proteins to attack and destroy it.
"What we've discovered is a brand-new trick up the sleeves of bacteria to evade this class of antibiotics," explains researcher Gerry Wright, who leads the McMaster-based Global Nexus for Pandemics and Biological Threats. "It's like a one-two punch. It's fascinating and it's so crafty."
The discovery shows that the mechanisms of antimicrobial resistance (AMR) are more complex and highly evolved than scientists had previously recognized.
Now Wright and his colleagues are combing their database of tens of thousands of samples to see if other bacteria use parallel processes and whether they reveal vulnerabilities that can be exploited to create urgently needed new antibiotics.
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Keywords: AMR _ antimicrobial resistance
Their work is described in a paper published online today in the influential journal Molecular Cell. Wright's co-authors are Matthew Surette, Kalinka Koteva and Nicholas Waglechner.
Wright says the discovery gives him with new respect for nature's adaptability and renews his enthusiasm for finding and exposing other methods bacteria use to ensure their survival.
"We've been facing this AMR problem for many years," Wright says. "Every time we think we've figured out all the ways bacteria resist antibiotics, along comes something like this, to let us know there are tricks we hadn't even thought of before."
AMR is a huge and growing global health concern that should be commanding much more attention and far more research resources, Wright says.
Though the effectiveness of penicillin, rifamycin and other established antibiotic treatments is waning quickly, most phamacy companies are not actively developing new antibiotics, he says.
Wright explains that drug discovery and development is tremendously expensive, and the financial return on investment in antibiotics would be low since they don't generate as much revenue as as prescription medication that patients use for years at a time.
AMR's threat to public health is simply too big to ignore, and requires collaboration between governments, universities and manufacturers, Wright says.
"We have to keep reminding people just how tricky these bugs are. We've all been focused on COVID these past two and half years, but AMR is still an enormous problem and these bacteria have continued to innovate and diversify their mechanisms of resistance," he says. "We have to keep working to make sure we really do understand the enemy."
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