STREPTOMYCIN
And other drugs to treat Tuberculosis
Surely Tuberculosis is a disease of the past?
You're thinking of Fantine, the character played by Anne Hathaway in the latest
version of Victor Hugh's Les Miserables. Sadly, TB is very much with us; around 1/3 of
the world's population is probably infected with it and it actually kills nearly 2 million
people a year. Most of these victims are in the developing world, so you don’t hear
much about them. There is a list as long as your arm of famous people killed by TB –
several of the Bronte sisters as well as other writers including Elizabeth Barrett
Browning, Anton Chekhov, Franz Kafka, John Keats and George Orwell; the
composers Frédéric Chopin, Luigi Boccherini and Giovanni Battista Pergolesi; the
actress Vivien Leigh, heroine of Gone With The Wind; Simon Bolivar the liberator of
Colombia, Venezuela, Ecuador, Peru and Bolivia; Saint Theresa of Lisieux; and King
Edward VI of England.
Following the Industrial Revolution, TB was a major cause of death in overcrowded
and insanitary cities, whilst a regular cause of death of a (fictional) heroine in opera,
just think of La Traviata, La bohème, The Lady of the Camellias and The Tales of
Hoffmann.
What causes it?
The scientist Robert Koch discovered the tubercule bacillus in 1882, winning the
Nobel Prize in Physiology or Medicine for this in 1905. TB is caused by a bacterium,
most usually Mycobacterium tuberculosis, a search for a cure went on for many
years. In the early 20th century, sanatoria to treat tuberculosis were a great step
forward, but the first drug effective against TB was not discovered until the 1940s.
And it can be treated?
Streptomycin was the first molecule active against TB; it was isolated by Albert
Schatz and Selman Waksman at Rutgers University in the United States.
Waksman’s family emigrated from the Ukraine to American when he was young. He
had originally been a student at Rutgers, moved to California to carry out the
research that led to his PhD, and later returned to Rutgers. He had a lifelong interest
in microorganisms in the soil, and the 1930s saw the discovery of the sulfa drugs, the
first antibiotic (MOTM July 2011), followed by penicillin. In 1939 Waksman started a
research programme studying study soil microorganisms that might have antibiotic
properties against pathenogenic bacteria.
Albert Schatz began working in Waksman’s laboratories in 1942; after a brief spell in
the US Army, where he began to look for antibiotics that could be active against
penicillin-resistant bacteria, from which he was discharged on health grounds, he
returned to Waksman, worked in a basement lab that could easily be isolated from
the rest of Waksman’s laboratories in the event of the bacterium escaping. Schatz
chose to work with a very virulent form of Mycobacterium tuberculosis, supplied by
William Feldman. Together with Corwin Hinshaw, Feldman worked at the Mayo
Clinic in Rochester, Minnesota, looking for antibiotics active against TB.
Schatz discovered two strains of a bacterium that made an antibiotic he called
streptomycin, which was active against Mycobacterium tuberculosis. Streptomycin is
in fact active against many pathogens. After Schatz and Waksman reported the
activity of streptomycin against tuberculosis in test organisms in 1944, Feldman and
Hinshaw showed that streptomycin would successfully treat TB in humans. Schatz
was to receive his PhD in 1945.
Both Schatz and Waksman were named on the application to patent streptomycin,
awarded in 1948. Waksman persuaded Schatz to sign over his rights to receive
royalties to Rutgers; subsequently he found out that Waksman had an agreement
with Rutgers to receive 20% of royalties, and also learned that Waksman was playing
down Schatz’s role in the discovery. Schatz successfully sued the Rutgers Foundation,
as well as Waksman, for a share of the royalties and recognition of his role in the discovery
of streptomycin. An out-of-court settlement in 1950 awarded Schatz $120,000 for the
foreign patent rights, and 3% of the royalties, representing about $15,000 per annum for
several years. However, when the 1952 the Nobel Prize in Physiology or Medicine was
awarded to Waksman "for his discovery of streptomycin, the first antibiotic effective
against tuberculosis", there was no mention of Schatz, nor of Feldman and Hinshaw,
who had shown that streptomycin was effective in human sufferers from
tuberculosis.
How does Streptomycin work?
It is an antibiotic which acts against a wide range of both Gram positive and Gram
negative bacteria (in contrast to penicillin, which only acts against Gram-positive
bacteria); it inhibits protein synthesis in the bacterium, binding to the rRNA in the
ribosome, distorting the ribosomal decoding site and inhibiting binding of tRNA.
So what's the problem?
For one thing, bacteria become resistant to streptomycin. Fortunately, other
molecules have been found to be active against TB. One of them is the simple
molecule PAS, para amino salicylic acid. Because PAS has a similar structure to 4aminobenzoic acid, which bacteria use to make folic acid, PAS was long believed to
interfere with this process by a similar means of action to the sulfa drugs, but now it
is thought that it acts on the folate pathway by generating molecules that are
poisonous to the bacterium.
Another of these is isonicotinic acid hydrazide (isoniazid); this inhibits cell wall
synthesis. It is a prodrug, and one active molecule it produces is NO, as does the
more recently discovered PA-824, which is still in the experimental stage.
There is also rifampicin, an antibiotic which blocks RNA synthesis.
Nevertheless, multi-drug-resistant TB is an increasing problem. The cause is partly
due to patients not completing courses of antibiotics; even though they are partly
cured, they still carry the bacterium. The bacterium is more easily spread due to
greater population mobility, as well as air travel. Many AIDS sufferers have severely
weakened immune systems and develop TB, which is responsible for ¼ of HIV
deaths. Multi-drug-resistant TB is a real problem.
Is there any hope of a treatment for that?
A molecule called Bedaquiline has just been approved for cases of this, though it
does have some possible side-effects in patients with cardiac arrythmias.
Bedaquiline works by targeting the proton pump for ATP synthase in the bacterium,
a different target to other anti-TB drugs.
Another experimental drug called Delamanid acts by inhibiting mycolic acid
synthesis, and trials indicate improved outcomes in patients with multidrug-resistant
TB.
One source of encouragement is that many drugs are now known that target the
bacterium in different ways, so that use of a cocktail of many of these offers real
hope.
But TB still can be a sentence of death?
It can be, but many have recovered from it, and their stories are often inspiring. Take
the Yorkshire cricketer Bob Appleyard. He took 200 first class wickets in the 1951
season, whilst unknowingly suffering from TB. In 1952 he was successfully treated
with streptomycin, then had surgery to remove the infected part of the lung, and
convalesced in 1953, so he missed two whole seasons’ play. He recovered his health,
and regained his form, despite reduced lung capacity, not just getting back into the
Yorkshire XI but being selected for England, helping them retain the Ashes in their
tour of Australia in 1954-5.
Bibliography
Books about TB and antibiotics
M. Wainwright, Miracle Cure: Story of Antibiotics, Wiley-Blackwell, 1990.
F. Ryan, Tuberculosis: The Greatest Story Never Told - The Search for the Cure and the
New Global Threat, Swift Publishers, 1992.
T. Dormandy, The White Death: A History of Tuberculosis, Hambledon Continuum,
1998.
J. Mann, The Elusive Magic Bullet, Oxford, OUP, 1999.
H. Bynum, Spitting Blood: The history of tuberculosis, Oxford, OUP, 2012.
P. Pringle, Experiment Eleven: Deceit and Betrayal in the Discovery of the Cure for
Tuberculosis, London, Bloomsbury, 2012 (Schatz’s notebooks)
Discovery of Streptomycin and its role
A. Schatz, E. Bugie and S. A. Waksman, Proc. Soc. Exp. Biol. Med., 1944, 55: 66-69; D.
Jones, H. J. Metzger, A. Schatz and S. A. Waksman, Science, 1944, 100, 103-105.
(discovery of properties)
W. H. Feldman and H. C. Hinshaw, Proc. Staff Meet., Mayo Clinic., 1944, 19, 593-599.
(effect on guinea pigs)
H. C. Hinshaw and W. H. Feldman, Proc. Staff Meet., Mayo Clinic., 1945, 20, 313-318;
H. C. Hinshaw, W. H. Feldman and K. H. Pfeutze, J. Am. Med. Assoc., 1946, 132, 778782; W. McDermott, C. Muschenheim, S. J. Hadley, P. A. Bunn and R. V. Gorman, Ann
Intern Med. 1947, 27, 769-822 (streptomycin and TB in humans)
J. H. Comroe, American Review of Respiratory Disease, 1978, 117, 773–781 and 957968. (story of streptomycin)
A. Schatz, Actinomycetes, 1993, 4, 27-39. (his account of the development of
streptomycin)
Streptomycin and how it works
F. A. Kuehl, R. L. Peck, C. E. Hoffhine and K. Folkers, J. Am. Chem. Soc., 1948, 70,
2325-2330 (structure of streptomycin).
H. Demirci, F. Murphy, E. Murphy, S. T. Gregory, A. E. Dahlberg and G. Jogl, Nature
Communications, 2013, 4, 1355 (how streptomycin works)
Other treatments for TB
D. D. Martin, F. S. Spring, T. G. Dempsey, C. L. Goodacre and D EW Seymour, Nature,
1948, 161, 435 (p-Aminosalicylic acid in the treatment of tuberculosis).
C. K. Stover, P. Warrener, D. R. VanDevanter, D. R. Sherman, T. M. Arain, M.H.
Langhorne, S. W. Anderson, J. A. Towell, Y. Yuan, D. N. McMurray, B. N. Kreiswirth, C.
E. Barryk and W. R. Baker, Nature, 2000, 405, 962-966 (PA 824).
K. Andries et al., Science, 2005, 307, 223-227 (discovery of bedaquiline)
M. Protopopova, E. Bogatcheva, B. Nikonenko, S. Hundert, L. Einck and C. A. Nacy,
Med. Chem., 2007, 3, 301–316. (TB cures, reviews)
A. M. Ginsberg, M.W. Laurenzi, D. J. Rouse, K. D. Whitney and M. K. Spigelman,
Antimicrob. Agents Chemother., 2009, 53, 3720-3725 (PA 824)
Q. Huang, J. Mao, B. Wan, Y. Wang, R. Brun, S. G. Franzblau and A. P. Kozikowski, J.
Med. Chem. 2009, 52, 6757–6767 (2-Methylbenzothiazoles as treatments for TB)
G. A. Marriner, A. Nayyar, E. Uh, S. Y. Wong, T. Mukherjee, L. E. Via, M. Carroll, R. L.
Edwards, T. D. Gruber, I. Choi, J. Lee, K. Arora, K. D. England, H. I. M. Boshoff and C.
E. Barry, Top. Med. Chem., 2011, 7, 47–124 (major review of chemotherapies for TB)
M. T. Gler et al, N. Engl. J. Med., 2012, 366, 2151-2160 (Delamanid)
J. Avorn, JAMA, 2013, 309, 1349- 1350 (FDA approval for bedaquiline)
A. Maxmen, Nature, 2013, 502, S4 – S6 (combinational therapy for TB)
V. Skripconoka et al., Eur. Respir. J., 2013, 41, 1393–1400 (Delamanid)
Other works cited
R. B. Mason, Can. Med. Ass. J., 1996, 154, 921-922 (TB and opera)
S. Chalke and D Hodgson, No Coward Soul, Bath, Fairfield Books, 2003. (Bob
Appleyard)
T. Paulson, Nature, 2013, 502, S2-S3 (worldwide distribution of TB)
Picture ideas (most well-known people have far more than one)
Anne Hathaway as Fantine
http://media.theiapolis.com/d8-iN04-k9-lP13/anne-hathaway-as-fantine-in-lesmiserables.html
(and many others)
George Orwell
http://img.dailymail.co.uk/i/pix/2007/09_01/orwellDM0509_468x417.jpg
Simon Bolivar
http://upload.wikimedia.org/wikipedia/commons/2/2f/Sim%C3%B3n_Bol%C3%ADv
ar_2.jpg
Keats
http://upload.wikimedia.org/wikipedia/commons/1/1a/John_Keats_by_William_Hilt
on.jpg
Chopin
http://upload.wikimedia.org/wikipedia/commons/3/33/Chopin,_by_Wodzinska.JPG
Vivien Leigh
http://upload.wikimedia.org/wikipedia/commons/0/0a/Vivien_Leigh_Gone_Wind_R
estaured.jpg
Robert Koch
http://upload.wikimedia.org/wikipedia/commons/9/99/Robert_Koch_BeW.jpg
Albert Schatz
http://static.guim.co.uk/sysimages/Admin/BkFill/Default_image_group/2012/6/26/1340720405968/AlbertSchatz-008.jpg
or http://blogs.haverford.edu/haverblog/files/2012/05/schatz001.jpg
Selman Waksman
http://upload.wikimedia.org/wikipedia/commons/3/33/Selman_Waksman_NYWTS.j
pg
Bob Appleyard
http://p.imgci.com/db/PICTURES/CMS/56800/56831.jpg
http://p.imgci.com/db/PICTURES/CMS/56800/56833.1.jpg