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Reimagining the AMR fight: Exploiting Fitness Costs
Antimicrobial resistance has been one of the most pressing issues in the healthcare sector in the 21st century and it is getting serious day by day, so much so that it is estimated to kill 40 million people by 2050. The bacteria, being very smart, does all in its power to ensure its survival, it just finds some way or the other to tackle the drugs that we have synthesized against them. Hence researchers all over the world are in the quest to find newer antimicrobials or modify the existing ones. Now, all this might sound scary and in a way it is. But at the cost of adapting to an antimicrobial, like an antibiotic, it doesn’t come easy, it comes with a cost. This is termed as ‘fitness cost’. Fitness cost is technically when the bacteria now, without the presence of an antibiotic is not able to grow as well as the wild type bacteria. Researchers at the Brown Lab, at McMaster University, Canada, exploited just that, that is the fitness cost it took for the bacteria to develop resistance to metallo beta-lactamase to tackle resistance in bacteria.
Carbapenems are a class of beta-lactam antibiotics that are used as the last-resort drugs to treat bacterial infections. But because of their overuse, bacteria developed resistance to these last-resort drugs, which is dangerous. The bacteria tackle the carbapenem drugs by producing carbapenemases, which are bacterial enzymes that break the backbone of carbapenem antibiotics. There are two kinds of carbapenemases, the serine beta-lactamases and the metallo beta-lactamases (MBL). There has been success in developing inhibitors that could make the bacteria susceptible to serine beta-lactamases, which in the vast majority of cases is by the inhibitor molecule modifying the serine group which helps in catalysis. But in the case of MBLs, there are currently no approved ones, and the potential ones (two inhibitors) are in their clinical trials. The work done in Brown Lab was specific to the MBLs. The MBLs need Zn(II) ions to activate a water molecule,which is basically when Zinc(II) ions when binding with water, helps to weaken the OH bond making it easier for the water molecule to lose a proton, which further could create the hydroxide ion (OHー) which is a much stronger nucleophile/electron donor. This reaction further helps the MBL in hydrolyzing or breaking down the beta-lactam ring. Hence in these MBL-producing bacteria, if the extracellular environment doesn’t have enough Zinc(II), it will affect the activity and even the stability of the MBL.
But what’s the catch here? The researchers targeted VIM-2, a type of MBL, and expressing this enzyme comes with a cost for the bacteria. VIM-2-expressing bacteria struggle to survive when there’s very little Zinc (II) around and they also put stress on the bacterial envelope. Now, this is useful as the susceptibility of drugs towards the bacteria can be increased. And in a way, this is revolutionary as well, that is instead of depending on the discovery of newer antibiotics, which could take years to come into the market, we could repurpose existing drugs to target these sort of hidden loopholes in resistance in resistant bacteria.
But how exactly does all this come into play? Well, as we know by now, VIM-2-expressing bacteria grow well in Zinc(II) rich conditions and not so well when in Zinc (II) poor environments. The researchers discovered that zinc is necessary for the VIM-2 enzyme to fold properly. Hence, in Zinc (II) poor conditions the enzyme could get misfolded in the periplasm and this would create a stress response in the bacterial cell, especially in the membrane. But how is this useful? Well, this would make the bacterial cell susceptible to drugs it wasn’t susceptible to before, as the membrane is now more permeable.
Enter, Azithromycin. This popular drug which is usually ineffective in gram-negative bacteria was tested against VIM-2-producing gram-negative Escherichia coli along with other classes of drugs. Azithromycin was chosen here because of its eightfold potency against VIM-2-producing E.coli. The reason why Azithromycin has poorer activity towards gram-negative bacteria is due to its poor cell penetration abilities. But in the case of VIM-2 expressing bacteria, the membrane is under stress hence, Azithromycin can penetrate well, so much so that the researchers observed a 26-fold increase in the intracellular accumulation of azithromycin in VIM-2-producing E.coli when compared to the ones not producing VIM-2.
This research sheds a new light and a new approach in tackling antimicrobial resistance research where the traditional focus has been on finding out new drugs. This research shifts our perspective to find out the effects that resistance has on bacterial physiology and target it accordingly to make use of the existing drugs available.
Link to the original post: Tu, M.M., Carfrae, L.A., Rachwalski, K. et al. Exploiting the fitness cost of metallo-β-lactamase expression can overcome antibiotic resistance in bacterial pathogens. Nat Microbiol 10, 53–65 (2025)
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