Fabimycin prevents growth for over 300 strains of drug-resistant bacterial clinical isolates, including E. coli, shown here.
Credit: SciePro/Shutterstock.com
It's a basic axiom of intelligent [sic] design creationism that evolution doesn't happen, so all change is the intentional design of a single creator (because, although they deny it's religion in disguise, the designer has to comply with basic Christian dogma, too, including a single creator god).
It that were true, news from the American Chemical Society, of a new drug that is proving to be effective against multiple drug-resistant bacteria, is a new challenge for Creationism's divine malevolence. It has been working hard, ever since the discovery of penicillin, to design ways in which its pathogens can continue to make us sick, by making them resistant to it and then to every other new antibiotic, in an arms race that looks exactly like the sort of evolutionary arms race that the Theory of Evolution by Natural Selection predicts.
Of course, Creation Inc. (no donation too large) has devised all manner of convoluted mental gymnastics for its followers to use to explain this apparent mendacity away and to portray the designer of these pathogens and their resistance as something else, because the real creator is infinitely benevolent and would like nothing better than having us all healthy and happy. The excuse usually includes blaming the victim or his/her ancestor/family, or humanity as a whole, or something someone once did thousands of years ago according to religious superstitions, while still pretending this is a scientific explanation, so ID creationism is real science, which should be taught to school children in science class at tax-payer's expense.
So, what exactly is this new drug and how does it work? The American Chemical Society (ACS) news release explains:
Urinary tract infections are common, yet are increasingly tough to treat because the bacteria that cause them are becoming resistant to many antibiotics. Now, in ACS Central Science, researchers report a new molecule that inhibits drug-resistant bacteria in lab experiments, as well as in mice with pneumonia and urinary tract infections. The researchers say that this compound, fabimycin, could one day be used to treat challenging infections in humans. Gram-negative bacteria are a class of microbes that infect millions of people worldwide, according to the U.S. Centers for Disease Control and Prevention, causing conditions such as pneumonia, urinary tract infections and bloodstream infections. These bacteria are especially difficult to treat because they have strong defense systems – tough cell walls that keep most antibiotics out and pumps that efficiently remove those antibiotics that get inside. The microbes can also mutate to evade multiple drugs. Furthermore, treatments that do work aren’t very specific, eradicating many kinds of bacteria, including those that are beneficial. So, Paul Hergenrother and colleagues wanted to design a drug that could infiltrate the defenses of gram-negative bacteria and treat infections, while leaving other helpful microbes intact. The team started with an antibiotic that was active against gram-positive bacteria and made a series of structural modifications that they believed would allow it to act against gram-negative strains. One of the modified compounds, dubbed fabimycin, proved potent against more than 300 drug-resistant clinical isolates, while remaining relatively inactive toward certain gram-positive pathogens and some typically harmless bacteria that live in or on the human body. In addition, the new molecule reduced the amount of drug-resistant bacteria in mice with pneumonia or urinary tract infections to pre-infection levels or below, performing as well as or better than existing antibiotics at similar doses. The researchers say the results show that fabimycin could one day be an effective treatment for stubborn infections.
Basically, bacteria can be classified as Gram-positive or Gram-negative, depending on whether they can be stained by the Gram stain and so identified under a light microscope. And that depends on the structure of the cell wall, with Gram-positive species having membranes that the stain molecule can pass through. As it happens, most pathogenic bacteria are Gram-negative, i.e., they have a tough, protective membrane. And the same characteristic also prevents an antibiotic molecule from getting inside the bacterial cell where it can do whatever it does, so the first trick in designing an antibiotic against Gram-negative pathogens is to make one which can get inside the bacterium.
The third trick is to avoid killing beneficial organisms.
The team used an inhibitor (Debio-1452) of an essential enzyme used by bacteria to synthesis structural fatty acids - FabI. Debio-1452 has parts which can be modified without affecting the bioactive section, as shown in the diagram on the left. The modification to emerge as the strongest candidate was the one with an amonium (NH3) group attached, which they called Debio-1452-NH3, or Fabimycin.
As they explain in the abstract to their open access paper in ACS Central Science, this has been shown to be effective in >200 clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, the so-called ESKAPE pathogens, and does not kill commensal bacteria.
AbstractIt looks like medical science has taken another step in the arms race between pathological micro-organisms and our attempts to prevent them harming us in what biologists call an evolutionary arms race. This will now create the environmental selection pressure which will benefit any mutations which can resist it, or as intelligent[sic] design creationists insist, the putative designer will now have two choices: it will either redesign these organisms to continue making us sick, or it will give up the competition and allow us to live with a little less suffering in the world.
Genomic studies and experiments with permeability-deficient strains have revealed a variety of biological targets that can be engaged to kill Gram-negative bacteria. However, the formidable outer membrane and promiscuous efflux pumps of these pathogens prevent many candidate antibiotics from reaching these targets. One such promising target is the enzyme FabI, which catalyzes the rate-determining step in bacterial fatty acid biosynthesis. Notably, FabI inhibitors have advanced to clinical trials for Staphylococcus aureus infections but not for infections caused by Gram-negative bacteria. Here, we synthesize a suite of FabI inhibitors whose structures fit permeation rules for Gram-negative bacteria and leverage activity against a challenging panel of Gram-negative clinical isolates as a filter for advancement. The compound to emerge, called fabimycin, has impressive activity against >200 clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, and does not kill commensal bacteria. X-ray structures of fabimycin in complex with FabI provide molecular insights into the inhibition. Fabimycin demonstrates activity in multiple mouse models of infection caused by Gram-negative bacteria, including a challenging urinary tract infection model. Fabimycin has translational promise, and its discovery provides additional evidence that antibiotics can be systematically modified to accumulate in Gram-negative bacteria and kill these problematic pathogens.Graphical Abstract
Erica N. Parker, Brett N. Cain, Behnoush Hajian, Rebecca J. Ulrich, Emily J. Geddes, Sulyman Barkho, Hyang Yeon Lee, John D. Williams, Malik Raynor, Diana Caridha, Angela Zaino, Mrinal Shekhar, Kristen A. Muñoz, Kara M. Rzasa, Emily R. Temple, Diana Hunt, Xiannu Jin, Chau Vuong, Kristina Pannone, Aya M. Kelly, Michael P. Mulligan, Katie K. Lee, Gee W. Lau, Deborah T. Hung, and Paul J. Hergenrother An Iterative Approach Guides Discovery of the FabI Inhibitor Fabimycin, a Late-Stage Antibiotic Candidate with In Vivo Efficacy against Drug-Resistant Gram-Negative Infections
ACS Central Science Article ASAP; DOI: 10.1021/acscentsci.2c00598
Copyright: © 2022 The authors.
Published by ACS Publications. Open access
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
Which Creationist thinks it will opt for the latter?
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