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Sat Oct 21, 2017, 08:42 PM

Front Lines in the Battle Against Antibiotic Resistance and a Posthumous Synthesis.

My favorite section heading title in the scientific review article I will discuss in this post, Natural Products as Platforms To Overcome Antibiotic Resistance (Wuest, Fletcher and Rossiter, Chem. Rev. 2017, 117, 12415−12474) is this one:

"Woodward’s Posthumous Synthesis of Erythromycin A."

Robert Burns Woodward is the only person to have synthesized Erythromycin A, which has this structure:



"Only person" is too strong a word; a better term would that Woodward's group is the only group to synthesize erythromycin A, the synthesis which was almost certainly largely designed by him, being completed by his students and post-docs after he died.

A nice internet riff on Woodward's synthesis of erythromycin A is here: Woodward Wednesdays

He did not, however, synthesize the drug after he died, although he was such a remarkable chemist, probably the greatest organic chemist ever, that one is inclined to think of him in quasi-mystical terms.

The completion of the work was conducted under Harvard Professor Yoshito Kishi, who had been one of Woodward's students.

Here is the final paper on this synthesis, published after Woodward died: Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin

Here is the triumphal remarks on the completion of the synthesis:

Completion of the synthesis of erythromycin was carried out in the following manner. Simultaneous deprotection of both the C-4” hydroxyl group of the cladinose moiety and the C-9 amino group in 7d by Na-Hg/MeOH13 furnished (9s)-erythromycylamine (l1a) [mp 126-129 OC, [.Iz5D -48.1’ (c 0.59, CHCl,); 75% yield] which was found to be identical with an authentic Me Me sample prepared from natural erythromycin by a known method.2O Treatment of loa with N-chlorosuccinimide (1 equiv) in pyridine at 25 OC gave 10b (mp 166-170 OC with partial melting at 130-134 “C), which was dehydrochlorinated by AgF in HMPA a t 70 OC to yield erythromycinimine ( 1 0 ~ ) Hydrolysis of 1Oc in water at 50oC afforded the corresponding ketone (40% overall yield from l0a), which was found to be identical with erythromycin (2) in all respects (‘H NMR, mp, mmp, CYD, mass, IR and chromatographic mobility).22


Here, from the review cited at the opening of the post is a scheme of Woodward's synthesis of erythromycin A:




Woodward, by the way was an interesting fellow. When he was 11 years old, in 1928, he wrote the German consulate in Boston to request copies of scientific papers relating to a class of chemical reactions now known as cycloadditions (specifically the Diels-Alder reaction). He entered MIT when he was 16 in 1933, was kicked out in 1934 for neglecting his studies, readmitted in 1935 and granted a bachelor's degree in 1936 and a Ph.D in 1937 when he was 20 years old. It is said he never actually had much interaction with his Ph.D. advisers, and barely knew them, their "adviser" status being a mere formality. He joined the faculty of Harvard University shortly after, remaining there until his death in 1979. Besides being the only person to successfully design a successful total synthesis for erythromycin A, Woodward was the only scientist to supervise a successful synthesis of vitamin B12. He was awarded the Nobel Prize in 1965.

Later on his life he worked with Roald Hoffman - who was born a Jew in Poland and was hidden in an attic from 1943 to 1944 (Anne Frank style) between the ages of 7 and 9 where his mother read him Geography texts - to formulate the Woodward Hoffman rules, for which Hoffman, a chemistry professor at Cornell University, was awarded the Nobel Prize in 1981, after Woodward died in 1979.

I have their book, one of my happiest possessions, in the original Verlag edition in my personal library with an inserted "errata" page in it, and the orbitals drawn in green and blue:




These rules govern the Diels-Alder reaction (and many other reactions) about which Woodward was inquiring when he was 11 years old.

As I remarked earlier in this space, one reason to do the synthesis of complex molecules is that such syntheses are high art, expressions of the beauty of the human mind:

A Beautiful Review Article on the Total Synthesis of Vancomycin.

Commercially erythromycin is not obtained by organic synthesis; it is isolated from cell cultures, a process which makes it about as cheap as aspirin, and it is still a widely used drug. (Woodward's synthesis involved 48 steps: A synthesis of this type would be commercially - and environmentally - prohibitive.) However, the species it kills are rapidly evolving, many resistant strains are known.

In Woodward's time, the goal of the organic synthesis of complex natural products was to prove their structure. Modern instrumentation coupled with modern software, high field NMR, high resolution mass spec, and x-ray and neutron diffraction systems have made organic synthesis less important in structural assignments.

Today, the goal of organic synthesis is less about structure and pure science and more about improving the "SAR" (structure activity relationships) of molecules that are modified versions of the natural products. Organic synthesis can also resolve in some cases drug shortages caused by the rarity of the species producing the natural product, an example being the anti-neoplastic (anti-cancer) drug Taxol, originally isolated from the bark of a slow growing yew tree in the Pacific Northwest, but ultimately provided commercially by partial synthesis from a precursor found in the far more plentiful pine needles of this tree. Another reason for modifying natural products is that they may not be optimized for use as drugs; they may exhibit unacceptable toxicity which needs moderation, or poor bioavailability, short half-lives in vivo, or poor stability.

So this is the goal of modern day synthesis of natural products, to improve upon nature to optimize natural products to serve humanity or to improve on their availability.

This long winded intro about R.B. Woodward brings me to the paper.

One of the many crises now before humanity is the fact that the effectiveness of antibiotics is being defeated by evolution, irrespective of whether the nut cases in the Republican party "believe" in evolution or not. (Evolution is not about "belief"; it is a fact and morons who cannot accept facts are, um, well, morons.) This evolution is being driven by overuse and by misuse, often on the part of patients, who stop taking their antibiotics when they start feeling better, even though some of the infectious organisms still survive in their systems, indeed, those organisms that have the strongest resistance to the antibiotic presented to defeat them. The consequences should be self evident.

Antibiotic development is not a big money maker in the pharmaceutical industry by the way. The industry makes more money on drugs that are palliative than drugs which cure diseases. A blood pressure drug that a patient is required to take for the rest of his or her life is going to make more money than a drug that cures a bacterial infection and only needs to be taken for a week or two.

A nice cartoon from the paper cited at the beginning of demonstrates the modes of action of almost all antibiotics now on the market:



Another graphic shows the number of people who get and die each year from infectious diseases that are resistant to antibiotics.



Figure 2. Total infections (gray) and deaths (black) in the US associated with various pathogenic bacteria.11 CRE = carbapenem-resistant enterococci; VRE = vancomycin-resistant enterococci; MDR =multidrug resistant.


Remarks from the introduction of the review article:

Among the greatest achievements of humankind in recent history stands the discovery and production of penicillin as a life-saving antibiotic. However, nearly a century of unchecked usage has rendered the world’s supply of antibiotics severely weakened; Sir Alexander Fleming noted in his Nobel lecture that underdosage can apply the selective pressure that induces bacteria to evolve resistance to these drugs. In this review, we contrast the traditional method of semisynthetic modifications to natural products with modern synthetic approaches to develop new antibiotics around the privileged scaffolds that informed drug discovery for decades in order to overcome contemporary antibiotic resistance. In the 90 years since the discovery of penicillin (1), natural products have provided a major foundation for the development of antibiotic drugs. The reliance on natural products to provide new molecular entities for virtually every disease is also well established.1 Of the nine antibiotic classes in Figure 1, six represent naturally occurring compounds, with only three (the sulfonamides, fluoroquinolones, and oxazolidinones) conceived entirely through synthetic chemistry. We note the impressive structural diversity and complexity within the natural product antibiotics especially when compared to the synthetic classes.

Scientists have warned for decades that bacteria are rapidly evolving resistance to antibiotics.2−4 Resistance has proliferated due to a confluence of two key factors: the frequent prescription against infections of a nonbacterial nature, such as viral infections, and unregulated usage, which can lead to sublethal doses, permitting resistance to spread rapidly.5 We also observe that prescribing habits vary drastically from country to country; the United States is particularly likely to use recently developed antibiotics rapidly, possibly shortening their lifetime of efficacy.6 Analysis of the IMS Health Midas database indicated that between 2010 and 2014 consumption of antibiotics worldwide increased by 36%;7 the carbapenems and polymyxins, two”last resort” drugs, have increased in usage by 45% and 13%, respectively. This resistance is extensively observed in hospitals where immunocompromised patients are particularly vulnerable. 8 Hospital-acquired resistant infections have spread rapidly since the initial discovery of sulfonamide- and penicillin-resistant strains shortly after the introduction of these drugs in the 1930s and 1940s.9,10 In the U.S. and U.K. this problem has not abated, as nearly 40−60% of hospital-acquired S. aureus strains are methicillin-resistant.11 These public health threats will continue to rise without new antibiotics and meaningful changes in treating infections. Beyond prescription in humans, antibiotics find extensive use as prophylactic agricultural supplements to promote livestock growth and prevent diseases. It is estimated that the US livestock industry consumes a staggering 80% of antibiotics produced.5 Antibiotic-resistant strains of Salmonella have been identified in ground meat,12 and antibiotic use in livestock has been strongly linked to fluoroquinolone-resistant Salmonella.1


The paper is 51 pages long, and regrettably I cannot reproduce it all in a post like this. The point of the article is a review of techniques that may address the utilization and semi-synthesis from natural products that show (out of evolutionary necessity) bacteriocidal effects.

It's chock full of beautiful synthetic schemes; if you can find your way to a good scientific library, and have a love and understanding of organic chemistry, an afternoon reading it might be really well spent.

One of the funnier parts of the article, well it would be funny were it not so awful, comes after the part just quoted above:

The need for new antibiotics is increasingly widely appreciated as a pressing concern by governments, scientists, and the general public.14,15 These factors, in tandem with the reduced research and development toward discovering new antibiotics, have worsened the recent eruption of antibiotic resistant bacterial populations across the globe. As the golden age of antibiotics has clearly ended, the most pessimistic view of the current state of affairs is that a postantibiotic era may be approaching.


The bold is mine.

Um, not your government. Your government is controlled by ignorant clowns and stupid people who hate science because they are not bright enough or educated enough to know a damned thing about it other than that they hate it. And while the neo-nazis in the White House and their racist pals in Congress may be slightly worse than the general public, the general public - and we need to include some people on the left as well, anti-vaxxers, anti-nukes and their ilk, anti-this, anti-that, in the set that has put this country well on the path to a post-scientific age.

The conclusion of the review begins with a restatement of what I said above:

In most talks given by natural product chemists, it is commonly noted that while natural products can have outstanding biological activities, they are often poor choices for drugs, exemplified by erythromycin. While semisynthetic modifications have historically redirected this potent activity into a clinically useful drug, we have demonstrated that the need for new antibiotics to overcome resistant pathogens is so great as to require new generations of drugs occupying previously unexplored regions of chemical space. We have shown herein that the most direct, efficient, and fruitful method of generating drugs that can evade bacterial resistance mechanisms is through the power of total synthesis. We have outlined synthetic achievements toward many antibiotic scaffolds, both traditional and unexplored, and have discussed how these compounds fare against pathogenic bacteria. Traditional SAR studies can be undertaken to identify the key bioactive moieties, which can then be modified to generate more potent compounds. Additionally, synthetic approaches such as DOS, FOS, and CtD can be used to construct unprecedented scaffolds bearing the complexity of natural products, despite that these molecules may be foreign to Nature to the best of our knowledge. We hope that the examples discussed herein will spark further inspiration in the synthetic community to continue exploring innovative targets and methods to ensure a sustainable antibiotic supply.


And it ends with this plaintive scientific call:

Despite the potential for new antibiotic isolates and scaffolds, we must take care to preserve the efficacy of drugs currently prescribed (and overprescribed!). This requires improving upon our antibiotic stewardship by encouraging reduction in both the over prescription and misuse of these medicines. We must also continue to educate the public about the causes and persistence of antibiotic resistance, in part to drive public favor for a greater allocation of resources to address this crisis. Although the recognition of the term “antibiotic resistance” has increased, the understanding of how to avoid it and how it is caused has not been translated as effectively.15 Only by actively combining scientific innovation and communication can we avoid a postantibiotic era.


I've bolded the line to wish the fine scientists who wrote this review good luck with that. We, in this country, have just established ourselves as a nation of morons, an international laughing stock with an educational system being directed by an Amway scanner who absolutely hates education.

I don't mean to be too depressing.

Have a nice Sunday in spite of me.

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