Infectious disease researchers at Cedars-Sinai Hospital have uncovered something even more disquieting about the methicillin-resistant Staphylococcus aureus (MRSA) bacteria. Far and away the most notorious (if not the most common) "superbug," MRSA isn't just resistant to its namesake penicillin-family antibiotics, it adapts itself to them, becoming stronger in the process. The Cedars-Sinai work, as described in the current Cell Host & Microbe, may ultimately offer new insights into what makes MRSA so powerful in the first place.
MRSA causes 80,000 invasive infections and 11,000 related deaths per year in the United States. That's not a great record, and, despite ever-increasing hospital sanitation efforts and new and better antibiotics, the bug remains a dire threat.
The origins of MRSA's myriad virulence factors—related to tissue adhesion, immune evasion, and host cell injury, generally— are not entirely clear, but together they pack a hell of a punch. A crew of pathogenic bacteria will move in and immediately get to work binding to host cells and tissue, stirring up every sort of inflammation, crushing the victim's immune system, building themselves a protective biofilm armor, and unleashing all sorts of toxins. It's a bad and often confounding scene.
"We should be able to steer clear of antibiotics that we understand may have the potential to exacerbate already bad infections"
We know that MRSA packs a resistance gene, called mecA, that blocks the interfering action of beta-lactam antibiotics, such as the penicillin family. The beta-lactams inhibit production of certain enzymes the bacteria needs to develop cell walls, leaving them vulnerable. Without this enzyme neutralized, the pathogenic bacteria is free to go about its business of reproducing like crazy and scorched-earth tissue invasion.
"MRSA is widely understood to be a pretty bad organism, and it is thought that it is somehow inherently more pathogenic than 'normal' S. aureus," David Underhill, the principle behind Cedars-Sinai's Underhill Laboratory and a co-senior author of the new study, told me. "While investigators have thought that this increased pathogenicity might be related exclusively to the presence of various toxins or other 'factors,' what our work suggests is that the very mechanism by which the bacterium becomes resistant to antibiotics makes it more inflammatory and damaging—in the presence of the type of antibiotic to which it becomes resistant."
In a sense, what the Cedars-Sinai team found is that the bacteria are more than just neutralizing the beta-lactams' cell wall-busting enzyme, they're learning from it. As it turns out, the beta-lactam antibiotics don't quite neutralize all of the bacteria's cell wall-building enzymes. They miss one in particular, called PBP2A.
The production of PBP2A is actually triggered by the presence of the beta-lactam antibiotics, so we can imagine it stepping in as a sort of replacement or surrogate. Like its neutralized forbearers, the enzyme enables the construction of cell walls by acting as a link or glue between different chains of proteins (a transpeptidase, properly), but these walls are different and more dangerous than other cell wells, according to the new study.
In particular, the new cell walls induce increased inflammation in the host, which means more tissue damage and more virulence all around.
So, the infection persists and in a worse form than had the infection been untreated. This poses a quandary to physicians. Most infections are treatable with beta-lactam antibiotics and they're thus administered as a first-line defense. If they don't work, then things escalate to different families of antibiotics known to be (relatively) effective against antibiotic-resistant bacteria.
Can't we just start with the alternative antibiotics? No, not really, or not usually. The beta-lactam antibiotics are overall the most effective treatments going and they also happen to be pretty cheap, relative to the newer ones. Starting with the alternative would mean missing most infections at the outset, which isn't really acceptable either.
Compounding things is that classifying a bacteria infection can take days, so most treatments are administered "blindly." It seems inevitable that, as things currently stand, some patients are going to wind up worse off and potentially with a poorer prognosis.
Perhaps we can still be more careful.
"I think the work can help us develop towards a more informed and effective choice of antibiotics," Underhill said. "We should be able to steer clear of antibiotics that we understand may have the potential to exacerbate already bad infections, and select ones that can be expected to be effective."