(TB)
affects approximately 10 million people every
year and causes around 1.7 million deaths worldwide.
‘Researchers have taken their first step towards developing a new, effective drug treatment for patients with drug-resistant tuberculosis in whom disease treatment is difficult.’
Many
strains of the
TB-causing
bacteria - Mycobacterium
tuberculosis - have developed resistance to the
first-line antibiotic treatment for TB, rifampicin.
Rifampicin-resistance is the resistance of the TB bacteria to
rifampicin with or without resistance to other anti-TB drugs.
There
are approximately 600,000 people every year who are diagnosed with
rifampicin-resistant tuberculosis. So the present
discovery
of a naturally occurring antibiotic, called kanglemycin A - related to the
antibiotic rifampicin - that is active against rifampicin-resistant Mycobacterium tuberculosis is definitely a significant one.
Hopefully, this compound and the enhanced
understanding gained from these studies may lead to effective new drug
treatments in the future.
The
findings of their study have been published in the journal
Molecular Cell.
Mechanism of
Kanglemycin A
Rifampicin acts by binding to a groove of an
enzyme known as RNA polymerase (ribonucleic acid polymerase) on
the bacteria. RNA
polymerase is the enzyme that synthesizes RNA, a
molecule essential in various biological roles like coding, decoding,
regulation, and expression of genes. If any mutations or changes occur in the amino-acid
sequence of the RNA polymerase, the binding is prevented, while the making of
RNA goes on.
The
structure of
Kanglemycin
A
is such that it binds to the same groove and also just outside the groove with
the help of some extensions. This kind of attachment allows it to
maintain its affinity or liking to the rifampicin-resistant
RNA polymerase and antibiotic activity in rifampicin-resistant bacteria.
Professor
Nikolay Zenkin, from Newcastle University's Institute for Cell and Molecular
Biosciences who led the study, said: "Treatment of TB involves a cocktail
of antibiotics administered over many months, and resistance to several key
antibiotics is becoming a major public health problem around the world. Our
findings are very exciting and the first step towards developing a new,
effective drug treatment for patients with rifampicin resistant TB to prevent
fatalities in the future."
Study
The
research team screened more than 2,000
extracts from filamentous soil bacteria to find out if they could inhibit cell
growth or prevent the production of RNA.
Kanglemycin
A proved to be effective against rifampicin-resistant RNA polymerases and also
managed to kill rifampicin-resistant Mycobacterium
tuberculosis.
The team used chemical, biophysical, molecular
biology and microbiological methods, as well as
X-ray crystallography to show how kanglemycin A binds
to its target RNA polymerase, inhibits the enzyme's mechanism and thus
continues to stay activeagainst the
drug-resistant bacteria.
X-ray
crystallography was used to characterize the interactions of kanglemycin A with
RNA polymerase.
The
results from this study will help to accelerate approval of kanglemycin A for
use in patients with TB, after its safety and efficacy have been proved in the
clinic.
Kanglemycin
A's approval will provide a rationale for the further development of new
antibiotics to combat drug-resistant Mycobacterium tuberculosis.
Reference :Hamed Mosaei, Vadim Molodtsov, Bernhard Kepplinger, John Harbottle, Christopher William Moon, Rose Elizabeth Jeeves, Lucia Ceccaroni, Yeonoh Shin, Stephanie Morton-Laing, Emma Claire Louise Marrs, Corinne Wills, William Clegg, Yulia Yuzenkova, John David Perry, Joanna Bacon, Jeff Errington, Nicholas Edward Ellis, Allenby, Michael JohnHall, NikolayZenkin, "Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis"
Molecular Cell (2018)
https://doi.org/10.1016/j.molcel.2018.08.028Source: Medindia
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