Antimicrobial resistance (AMR) is one of the top global public health and development threats. It is estimated that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths. AMR puts many of the gains of modern medicine at risk. It makes infections harder to treat and makes other medical procedures and treatments – such as surgery, caesarean sections and cancer chemotherapy – much riskier. If this was not solved there would be an antibiotics pipeline and access crisis. There is an inadequate research and development pipeline in the face of rising levels of resistance, and urgent need for additional measures to ensure equitable access to new and existing vaccines, diagnostics and medicines. In addition to death and disability, AMR has significant economic costs. The World Bank estimates that AMR could result in US$ 1 trillion additional healthcare costs by 2050, and US$ 1 trillion to US$ 3.4 trillion gross domestic product (GDP) losses per year by 2030.
“The beauty of this antibiotic is that it kills through two different targets in bacteria,” said Alexander Mankin, distinguished professor of pharmaceutical sciences at UIC. “If the antibiotic hits both targets at the same concentration, then the bacteria lose their ability to become resistant via acquisition of random mutations in any of the two targets.”
Macrolones are synthetic antibiotics that combine the structures of two widely used antibiotics with different mechanisms. Macrolides, such as erythromycin, block the ribosome, the protein-manufacturing factories of the cell. Fluoroquinolones, such as ciprofloxacin, target a bacteria-specific enzyme called DNA gyrase.
Two UIC laboratories led by Yury Polikanov, associate professor of biological sciences, Mankin and Nora Vázquez-Laslop, research professor of pharmacy, examined the cellular activity of different macrolone drugs.
Polikanov’s group, which specializes in structural biology, studied how these drugs interact with the ribosome and found that they bind more tightly than traditional macrolides. The macrolones were even capable of binding and blocking ribosomes from macrolide-resistant bacterial strains and failed to trigger the activation of resistance genes.
Other experiments tested whether the macrolone drugs preferentially inhibited the ribosome or the DNA gyrase enzymes at various doses. While many designs were better at blocking one target or another, one that interfered with both at its lowest effective dose stood out as the most promising candidate.
Studies show the cost of resistant infection ranges is up to about $30,000 per patient episode (2020 dollars and costs). On average people stay an extra 7.4 days in the hospital and the odds of dying nearly double (1.84 times) and there is about 1.492 increased readmission likelihood.
Abstract
Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.
“By basically hitting two targets at the same concentration, the advantage is that you make it almost impossible for the bacteria to easily come up with a simple genetic defense,” Polikanov said.
Brian Wang is a Futurist Thought Leader and a popular Science blogger with 1 million readers per month. His blog Nextbigfuture.com is ranked #1 Science News Blog. It covers many disruptive technology and trends including Space, Robotics, Artificial Intelligence, Medicine, Anti-aging Biotechnology, and Nanotechnology.
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They will synthesize it in China and feed it to the pigs as growth enhancers by the kilo, and in 2 years it will be as ineffective as all the other antibiotics.
They claim it’ll be 100 million times harder for bacteria to adapt to it. If they’re right, then if it took two years for existing antibiotics, it’ll take 200 million years for this one.
Seems expensive with difficult logistics and heavy infrastructure. I imagine that the poor will expect to be given it for free. I always felt that expensive and highly-complicated technologies that will transform societies, but couldn’t easily trickle-down, could lead to significant conflict and chaos.
As long as it costs less than $30,000 for a course of treatment, an insurance company will be more profitable if it pays for this.
If this is delivered into the gut, it will wipe out friendly flora and whether you like it or not, spores from the air will take root and replace the missing friendly flora, resulting in conditions like SIBO and other forms of dysbiosis. From there you can get to any kind of insulin resistance, autoimmunity, allergy and neurodegenerative condition.
Treating an infection isn’t just about waging war on a bad pathogen. You have to protect the good flora too – often these send crucial signals to regulate your metabolism and innate defenses, so taking them out actually leaves you *more* vulnerable to future infections. (Take a look at how butyrate production or TAS2R38 functions.) This is how I wound up with arthritis and sinus infections my whole adult life.
You don’t have a choice about hosting organisms. The question is which ones.
And many of the negative effects of processed food arise from killing friendly flora and feeding toxic ones instead. If this is delivered into the gut, it will wipe out friendly flora and whether you like it or not, spores from the air will take root and replace the missing friendly flora, resulting in conditions like SIBO and other forms of dysbiosis. From there you can get to any kind of insulin resistance, autoimmunity, allergy and neurodegenerative condition.
Treating an infection isn’t just about waging war on a bad pathogen. You have to protect the good flora too – often these send crucial signals to regulate your metabolism and innate defenses, so taking them out actually leaves you *more* vulnerable to future infections. (Take a look at how butyrate production or TAS2R38 functions.) This is how I wound up with arthritis and sinus infections my whole adult life.
You don’t have a choice about hosting organisms. The question is which ones.
And many of the negative effects of processed food arise from killing friendly flora and feeding toxic ones instead.
Meh. All medical interventions are triage and risk assessment. Death or illness/ incapacitation. Dignity or functionality. Disfigurement or dysfunction. Reduced life span or increased temporary quality of life. The key is to always pursue a second opinion when you have time to get one. Genes are your biggest risk/functionality factor – but that’s assuming a lifestyle of reasonable prudence. Family history, all those major check-ups at 40s , 50, 60, 80s – before symptoms appear – common sense and good insurance.
The proper solution to that is just following up administration with appropriate bacterial cultures once the antibiotic has cleared your system. This isn’t terribly difficult to do.
In fact, that one-two combination would probably resolve a lot of problems people with the wrong intestinal flora experience.
Sounds great, so why isn’t it done ? Maybe not so easy?
We do in fact prescribe broad-spectrum antibiotics, and follow up with probiotics. Antibiotics have saved countless lives.
It’s not nearly as easy as you think and you shouldn’t be telling people that it is. Many of the species killed in the gut can’t be replaced with a commercial source short of a surgical fecal transplant, which itself carries great risks.
Between the omnipresent antibiotic use and the bad diets, the ecological diversity in the human gut is in terminal decline and this is creating an ever-increasing burden of disease from one generation to the next.
This narrowing of ecological diversity is one of the factors contributing to the risks that ratchet up with each new Covid infection. Covid knocks out antimicrobial production in the gut, leading to dysbiosis. This then creates diseases that put patients at greater risk for the next Covid encounter (e.g., obesity, insulin resistance, etc.). Get another infection and there’s more damage to the gut flora. (A similar snowballing occurs with cumulative damage to sulfur metabolism.)
Which is exactly what the data on third and fourth infections is showing – ever greater odds of long covid, stroke, cancer, etc… (Yes, Covid causes cancer directly by interfering with cell division and it sabotages the immune system’s normal scavenging of cancer by exhausting NK cells and T-cells.)
A probiotic worked for me.
I had a urinary tract infection and took an antibiotic to deal with that. Then I had bowel problems. Eating yogurt only helped a little. I took a probiotic a pharmacist recommended ( Florastor FWIW) and I now have essentially zero cases of the runs, which hadn’t been the case for quite a few years.
Yes I know.
Anecdotal evidence. YMMV
BTW why couldn’t I edit the comment after I posted it.
Man if this where the case global, cancer was on the rise as spacex launch shemed in the charts…
It is not.
Everything’s a tradeoff. I don’t want to go back to the world where any surgery had a serious risk of killing you from infection. Even small cuts used to kill people sometimes.
We definitely should use antibiotics more judiciously than we do, but sometimes they’re worth it and when they are, it’d be nice if they worked.
The ability to resist adaptation by a factor of 100 million will buy us a little time to come up with the next scheme.
What does this do to good gut bacteria?
Sounds good, but what effect will it have on the mitochondria? Super “Cipro” could be a horror show for some susceptible people. Unless they run an enriched enrollment study and exclude negative responders. In which case it could be a goldmine. Call me a convincable skeptic, but a skeptical foremost.
Humans basically all have exactly the same mitochondria, except for some poor souls with mitochondrial genetic diseases. And the ribosomes they rely on are quite different from bacterial ribosomes, in that they rely on proteins encoded in the nuclear DNA.
So assuring that this wouldn’t wipe out your mitochondria wouldn’t be difficult, as it would likely either effect everybody’s mitochondria, or nobody’s.
Nice to read, I always understood big pharma wasnt interested enough because of low profits, this really is in the very beginning of the research it seems! Curious what testen will bring, would a two pathway working agent be more beneficcial towards safety in human test phases?