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How Single-Atom Changes Overcome Antibiotic Instability

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For those of us who are scientists, organic synthesis is one of the most powerful tools at our disposal. With advanced knowledge of chemical reactivity and a creative spirit, one can synthesize any molecule they wish with ease. Arguably, some of the most important molecules manipulated by scientists are those with clinically-relevant activity. Fostering collaboration between chemists and biologists results in some of the most profound advances in medicine. Powerful examples of these efforts can be found in the field of antibiotics. Through iterative refinement of complex compounds, interdisciplinary teams of synthetic chemists and microbiologists have reimagined the field of antibiotic drug discovery. Taken on an even smaller scale, substitution of just a single atom in a given molecule can have profound effects on its chemical and biological properties. The story herein highlights the extraordinary abilities we have to transform seemingly-hopeless molecules into highly-successful drugs, with a particular emphasis on antibiotics.

Despite the wide array of chemical reactions in our toolbox, it’s not uncommon that a synthetic chemist dreams up a desired compound but lacks the existing chemistry to make such a modification. This is exactly the kind of problem Gademann’s team at the University of Zurich sought to solve. They started with the goal of modifying a molecule called fidaxomicin, which is an antibiotic that was approved by the FDA in 2011. Fidaxomicin is recommended for the treatment of Clostridioides difficile, a bacterial infection that causes severe gastrointestinal distress. Concerningly, resistance to fidaxomicin was already rising in the clinic and still continues to grow today, negating its therapeutic use. Additionally, fidaxomicin is unstable under acidic conditions, a physicochemical property that is essential to a successful drug targeting any stomach infection. The instability of fidaxomicin is attributed to its acid lability, which refers to the ability for a bond to be broken easily.

The researchers identified that the site of acid lability was an oxygen atom. Oxygen (O) can act as a hydrogen (H) bond acceptor, meaning it is protonated in acidic environments to form an O-H bond. In this case, protonation of its oxygen atom causes the molecule to degrade, cleaving an essential bond that holds two halves of fidaxomicin together. Sulfur (S) atoms, on the other hand, are not as readily protonated. The reason for this comes down to atomic size – sulfur atoms are larger than oxygen atoms, and the larger the atom the weaker the bond. When a sulfur atom gets protonated, the S-H bond breaks easier than the bonds that hold together fidaxomicin, whereas an O-H bond is harder to break in the presence of acid than the molecule itself. Therefore, the researchers set out to replace the oxygen with a sulfur atom, which they hypothesized would afford a molecule that is stable under acidic conditions and, as a result, would survive the conditions of the stomach.

Unfortunately, typical conditions to exchange an oxygen for a sulfur atom involve acid, undergoing a mechanism in which fidaxomicin falls apart. Instead of giving up, a new strategy was invented to perform the single-atom substitution. The researchers discovered that they could intercept fidaxomicin’s degradation by “trapping” the intermediate compound with a sulfur-containing basic molecule. Excitingly, their proposal was a success and the sulfur-modified fidaxomicin was significantly more stable under acidic conditions, offering a promising solution to fidaxomicin’s current limitations.

Not only will this novel reaction enable synthesizing stable derivatives of fidaxomicin, but it can also be applied to other molecules in which oxygen-to-sulfur substitutions are required. Furthermore, there are a multitude of examples that feature the power of single-atom changes in having profound effects on drug-like properties (see the additional sources). By continuing to uncover unique ways to manipulate molecules we progress toward safer, stabler, and wider-reaching therapeutics. With the threat of growing antimicrobial resistance on the rise, broadening the landscape of drug compounds and introducing chemical diversity into the clinic is as important as ever.

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Featured image: Isabella Ferrara et al (2024)

Additional sources:
To read more about Clostridioides difficile infections, click here.
To see the FDA approval for fidaxomicin, click here.
To read a recent review on single atom substitutions by Dale Boger’s group at the Scripps Research Institute, click here.