IISc: Repurposing existing drugs to fight TB
Small changes to the molecules can turn them into effective TB drugs
A proof-of-concept study has successfully identified two small molecules (imipramine and norclomipramine) that can arrest the growth of TB bacteria and hence have the potential to be used as anti-TB drugs once the chemical properties are altered to make it more effective.
Interestingly, one of the small molecules (imipramine) is already in clinical use as an antidepressant while other is a metabolite of antidepressant clomipramine. But, they have never been used as antibacterials.
The two small molecules work by targeting the Topoisomerase I enzyme of the TB bacteria. This enzyme is essential for controlling the coiling (winding) and uncoiling (unwinding) of the bacterial DNA. The results of the study were published recently in the journal Antimicrobial Agents and Chemotherapy.
“We have for the first time found the inhibitors that prevent the enzyme from functioning. The inhibition of the enzyme arrests the growth/division of the bacteria and eventually causes death,” Prof. V. Nagaraja of the Department of Microbiology and Cell Biology, Indian Institute of Science (IISc), Bengaluru and the senior author of the paper told this Correspondent. He led the team that identified the inhibitors.
Though the two molecules inhibited cell growth by preventing DNA coiling, the potency was not high enough. “The inhibition is not as effective as drugs that are already being used as anti-TB drugs,” he said.
He has been working on this enzyme for a long time. This class of enzyme is found in all bacteria and even in higher organisms like mammals and humans. But human Topoisomerase I enzyme has properties and functions that are very different from that of bacteria. And inhibitors for human Topoisomerase I enzyme have already been identified and successfully exploited, as in the case of cancer drugs. “But there has been no such progress in the case of bacteria, as inhibitors of bacterial Topoisomerase I enzyme were not identified so far,” Prof. Nagaraja said.
Even in the case of bacterial Topoisomerase II enzyme, inhibitors have long been identified and clinically-validated drugs such as ciprofloxacin and other members of the fluoroquinolones are widely in use today. Since the small molecules studied are being routinely used as antidepressants, it may not be possible to use them as anti-TB drugs in the current form.
However, small changes in the chemical entity of the molecules can change the properties and activities dramatically. “This has to be done in this case,” he said. “The current study only highlights the potential of repurposing or redesigning existing drugs that are not antibacterials as anit-TB drugs.”
As no X-ray crystal structure and, hence, atomic details of the enzyme is available, a 3D structure of the enzyme was modeled by the co-author Dr. Sean Ekins of Collaborative Drug Discovery, a company based in California.
The molecules that can be likely candidates were first identified through virtual screening of many compound libraries. Further studies were then carried out in the laboratory of Prof. Nagaraja to find their inhibiting properties.
The identification of the two small molecules was part of the TB consortium project “More Medicine for TB’s” (MM4TB) with the larger goal of screening small molecules as potential anti-TB drugs. The MM4TB is an international consortium that has been assembled by the EU to discover new treatment methods to combat TB.
Why stars feast and fast partly resolved
Supergiant fast x-ray transients (SGXT) are in the news. SGXT is the name for a certain type of binary star — a pair of stars revolving around each other.
To be specific, they are a pair in which one partner is a big bright star and the other is a highly condensed dark companion — a black hole or a neutron star — which attracts mass from the bright star.
As the material spirals into the dark star, it emits x-rays. Hence, it appears to the onlooker that they are shining brightly in x-rays.
Suddenly, without warning, the pair dims to a fraction of its brightness within minutes. This behaviour of shining and dimming, called “fasting” and “feasting” has puzzled astronomers for a decade now.
This puzzle has now been partly resolved by means of a breakthrough, thanks to the work of an international team led by Varun Bhalerao of the Inter University Centre for Astronomy and Astrophysics, Pune. The results were published recently in the journal Monthly Notices of the Royal Astronomical Society.
There were several competing theories as to why the fasting and feasting behaviour happens. One is that the large star gives out a clumpy wind, and when this wind hits the dense star, it would glow.
The other theory is that the dense star has a high magnetic field and this served as a barrier that would dam the wind until the pressure built up and broke the “dam” and the matter carried by the wind would suddenly fall into the compact star, causing a glow.
Varun Bhalerao’s team observed the magnetic field of the dark companion and actually measured it, finding it to be too weak for the damming mechanism to work. “We knew that the key to the puzzle was to measure the neutron star's magnetic field,” he says.
Dr. Bhalerao’s team observed the binary using a space x-ray telescope known as NuStar, a NASA space mission. It is the first x-ray space telescope that can focus on very high energy x-rays.
“NuSTAR is used to study the most extreme environments in the universe, which emit x-rays.
“The x-rays that NuSTAR is sensitive to are similar to the x-rays used in hospitals for diagnoses. Astronomers call them ‘Hard x-rays’. During my Ph.D at Caltech [California Institute of Technology], I was part of the team that built NuSTAR's detectors,” he says.
The actual star-pair they observed, IGR J17544-2619, is an example of such an SGXT. It is a binary located about 12,000 light years away from the earth. It contains a supergiant star, about 25 times as massive as our Sun, and a compressed dead partner, about twice as massive as the Sun but compressed to a diameter of just about 30 km. the stars orbit around each other in 4.9 days.
The binary shines in x-rays and over a period of months can sporadically become bright or faint. The brightest known state was about one lakh times brighter than the dim state.
The discovery of the mechanism of fasting and feasting process is the breakthrough that many were looking forward to and has given important inputs for further theoretical understanding of these binaries. Says Dr Bhalerao: “This allows us to better understand how massive stars form, to study how binaries evolve and to calculate details of supernova explosions, where a neutron star is born in the death of a massive star.”
An entire village shuns using chemicals for growing crops
Farmers in Sorapattu village of Mannadipattu in Puducherry seem to have a lot of information on using integrated pest management (IPM) for protecting their crops rather than using chemical pesticides for the same.
IPM means judicious combination and use of all locally available pest control agents. All the farmers in the village have invariably curtailed the use of plant protection chemicals and started following practices like using neem oil, neem cake, tricho cards, light trap, pheromone trap, and ‘T’ shaped bird perches, thus helping them save more than Rs.5,000 per hectare towards crop protection (before they adopted this the cost was about Rs.6,800)
Since 1994
The emphasis on IPM in the region has been in practice since 1994, in order to bring down the indiscriminate usage of pesticides to contain crop pests and diseases while conserving and protecting natural insects in crop ecosystem.
Perunthalaivar Kamaraj Krishi Vigyan Kendra (PKKVK), Puducherry, in co-ordination with the agriculture department has been responsible in bringing this tremendous change in the attitude of the farmers towards this method.
Pesticide consumption in this region has come down significantly from 163 metric tonnes in 1990-91 to 40.92 tonnes in 2013-2014, resulting in a two-thirds reduction in its consumption. Similarly, the number of pesticides outlets has decreased from 196 in 1990-1991 to 115 in 2013-2014, nearly a 30 percent decrease.
Lowest number
The lowest number of outlets was recorded in 2006-07 & 2007-08, according to Dr. N.Vijaykumar, subject specialist, who has been conferred nearly half a dozen awards by different sectors for his work on this subject.
“The concept has spread well and widely accepted by the farming community. The scripting success on its adoption, the strenuous efforts and consistent follow-up confirm that farmers have realised the ill-effects of chemicals in various crops which include rice, groundnut, cotton, coconut, banana, vegetables, flowers and sugarcane over years,” says Dr. Mohan Saveri Programme Coordinator.
During the past 17 years between 1997 and 2014 a total of 69 training programmes were conducted involving more than 2,000 participants.
Over the years, the duration of the trainings ranged from one to five days and more number of trainings conducted among different crops. Emphasis was placed on seeing is believing, teaching by doing and learning by practicing in these training sessions.
Apart from the regular training, field visits and farm advisory services were also carried out.
Different channels
The success achieved in popularising these technologies is mainly due to the creation of awareness and transferring skills through participatory as well as farmer to farmer mode, by conducting farmers’ field schools, imparting training, printing and distribution of leaflets and pamphlets, conducting demonstrations and rendering prescription support farm advisory services.
The Kendra took on the responsibility of making available different bio agents and bio control inputs for the farmers since sourcing them on time could prove very time consuming and laborious.
The green revolution laid more emphasis on producing quantity and this led to indiscriminate and over use of chemical insecticides to control insect pests and produce higher yields.
Past decade
But in the past decade increasing awareness on the toxin residues on the crops and the need for a safe and efficient alternative which can help farmers cut costs and at the same time produce healthy food is fast finding acceptance among both the sectors, according to Dr. Mohan Saveri, Programme Coordinator of the Kendra.
The Indian Council of Agricultural Research, New Delhi had conferred the Kendra with the best KVK award for promoting IPM through Integrated extension approaches to the farming community.
Clutch and gearbox turn up in insect flight
Insects can be pesky creatures, with flies and mosquitoes able to skillfully avoid attempts at swatting them away. Their ability to fly — and manoeuvre dexterously — is made possible by some remarkable adaptations they possess, including a clutch and even a gearbox, according to research from a team of Indian scientists.
Insects are the most successful organisms to inhabit the earth, notes Sanjay P. Sane of the National Centre for Biological Sciences (NCBS) in Bengaluru. They were the first living things that evolved the ability to fly. Mastery of the air, along with miniaturisation of their bodies, gave them incredible access to ecological niches that other animals could not reach.
But such miniaturisation also made flight more challenging. The laws of aerodynamics demand that the smaller an animal becomes, the faster it must flap its wings in order to fly, remarked Dr. Sane.
Houseflies and fruit flies flap their wings at between 200 to 300 times a second, with each wing stroke being carried out in about four to five milliseconds. A blink of an eye, on the other hand, takes about 150 milliseconds. “We are extremely slow compared to insects,” he said.
To remain airborne, flies must synchronise the movement of their wings as well as those of a pair of sensory organs (one on each side) known as halteres. The halteres, which are essential in giving insects a sense of their orientation as they fly, move in the opposite direction as the wings.
In a paper published this week in the Proceedings of the National Academy of Sciences (PNAS), Dr Sane, along two students in his lab, examined how flies coordinate the movement of their wings and halteres at such high rates of flapping. Nerve cells would be far too slow for this purpose.
When the wing of a dead fly was manually manipulated, the wing on the other side also moved as did both halteres, showing that mechanical linkages were involved. Using the soldier fly, Hermetia illucens, Tanvi Deora, a graduate student and the paper’s first author, was able to painstakingly figure out what those connections were.
A structure in the insect’s thorax, the scutellum, linked its wings. The wing and haltere on each side were connected by another structure, the subepimeral ridge.
However, a fly is also able to move just one wing. During courtship, for instance, a male fruit fly vibrates a wing to create a distinctive sound for attracting females.
It turned out that the insects utilised a ‘clutch’ mechanism to engage and disengage a wing from the thoracic coupling used to coordinate wing and haltere movement. This clutch was controlled by nerve cells, said Dr. Sane.
In another remarkable similarity with automobile transmission systems, flies also had the insect equivalent of a gearbox at the base of each wing. An imaging system set up by Amit Kumar Singh, the paper’s second author and now a graduate student in Australia, showed the gearbox in action.
This gearbox has four modes, with one mode used during the insect’s resting state and the other three during flight. The flight modes set how far up and down the wings could move, thus varying the force they created.
The ability to change modes in mid-flight appeared to be under the insect’s neuronal control, according to Dr. Sane. A fly may be setting different modes on its two wings so that it could turn and manoeuvre rapidly, he added. Bees and beetles too use similar mechanisms for flight, said Ms. Deora
Deadly TB strains emerged in Asia over 6,000 years ago
In a path-breaking find, an evolutionary geneticist from the National Museum of Natural History in Paris has decoded the tuberculosis (TB) genome, suggesting that a pernicious family of the strain emerged in Asia over 6,000 years ago.
The study of nearly 5,000 samples of Mycobacterium tuberculosis from around the world showed how a lineage of the bacterium that emerged thousands of years ago in China has since become a global killer, widely resistant to antibiotic drugs, the Nature Genetics reported.
The evolutionary geneticist Thierry Wirth and his team analysed 4,987 samples of the “Beijing lineage” from 99 countries, fully sequencing the genomes of 110 of them and more limited stretches of DNA in the rest.
The researchers then used the information to date the expansion of the lineage and show how the strains are related.
“Consistent with its name, the “Beijing lineage” did emerge near north-eastern China. And it did so around 6,600 years ago which coincides with archaeological evidence for the beginnings of rice farming in China’s upper Yangtze river valley,” Wirth noted.
Although M. tuberculosis, probably, first emerged some 40,000 years ago in Africa, the disease did not take hold until humans took to farming with the consequent settling down.
“The grouping of people in settlements made it easier for the respiratory pathogen to spread from person to person,” Wirth pointed out.
Of all the M. bacterium strains circulating today, few strike more fear in public-health officials than the Beijing lineage.
First identified in greater Beijing in the mid-1990s, this lineage now circulates throughout the world and many strains are resistant to drugs that vanquish other types of TB. The increasing availability of antibiotics in the 1960s, meanwhile, coincides with a fall in the numbers of the bacterium.
The lineage rebounded, however, in the late 1980s and early 1990s.
Since it emerged, the “Beijing lineage” has become much more infectious, Wirth says, so it out-competes other strains of the bacterium.
His team identified mutations related to antibiotic resistance, metabolism and evasion of immune responses that may have contributed to the success of the “Beijing lineage”.
Uttarakhand becomes No. 2 in tiger population
Uttarakhand with 340 tigers is second only to Karnataka, which has 406.
Tiger population in Uttarakhand has risen from 227 to 340 since the last census, becoming the second State in the country after Karnataka with the highest number of tigers.
“There has been an encouraging rise in tiger population in Uttarakhand. It has risen from 227 to 340 since the last census. This is all the more creditable given the fact that the hill State has just one tiger reserve,” Corbett Tiger Reserve Director Samir Sinha told PTI.
There was a time when Madhya Pradesh had the highest tiger population in the country but then it had six tiger reserves, he said.
Uttarakhand is now second only to Karnataka in terms of tiger population. Karnataka figures at the top of the list with 406 tigers, he said.
As per the latest census, Corbett Tiger Reserve has also improved its position on conservation assessment trajectory going up from good to very good, the official said.
According to the latest census released on Tuesday, the tiger population in the country is estimated to be around 2,226, a rise of over 30 per cent since the last count in 2010.
Javadekar seeks transboundary cooperation to develop Himalayan region
Increased transboundary cooperation was needed to transform mountain forestry in Hindu Kush Himalayan region, Union Environment Minister Prakash Javadekar, who addressed the inaugural session of the five-day symposium on ‘Transforming Mountain Forestry’ said, on Sunday.
The symposium, which began on Sunday, aims at creating conducive transboundary conditions, politically and institutionally, to protect the forest ecosystems in the Hindu Kush Himalayan region.
Mr Javadekar, who addressed the gathering through his video-recorded message, said, “The symposium gives an opportunity to share the best practices. It is important for the stakeholders in the entire Hindu Kush region to promote sustainable and inclusive forest management that brings together practice, policy, and science. There are also transboundary issues (that need to be addressed).”
The symposium, which is being jointly organised by the Dehradun-based Forest Research Institute and the Kathmandu Valley-based International Centre for Integrated Mountain Development (ICIMOD), is the first to focus on the mountain forestry in the Hindu Kush Himalayan region.
Director General of ICIMOD David Molden also stressed on the need for transboundary cooperation regarding forest issues and called for collective efforts to make Reducing Emissions from Deforestation and Forest Degradation (REDD-plus) a reality.
The objective of the symposium is: ‘To outline options for sustainable forest management practices and policies that address the changing conditions in the Hindu Kush Himalayas while identifying transboundary opportunities that meet climatic and contemporary challenges, thus simultaneously addressing conservation and inclusive development.’
Over 200 regional and global experts from countries including United States of America, Germany, China, Pakistan, Afghanistan, Bhutan, Nepal, and Italy with participants including cross sector policy makers, scientists, practitioners, donors, market actors, legal experts, forestry professionals and representatives from the business and civil society will be present at the five-day symposium.
Centre to reconsider ESZ notification
The Centre has agreed to reconsider the December 18, 2012 eco-sensitive zone (ESZ) notification according to which a 100-km stretch of the Bhagirathi from Gaumukh to Uttarkashi— covering an area of 4,179.59 sq km— was to be declared as eco-sensitive.
A team headed by Uttarakhand Chief Secretary N. Ravi Shanker met Nripendra Misra, Principal Secretary to Prime Minister Narendra Modi, on Tuesday in New Delhi and requested the Centre to withdraw the ESZ notification.
Mr. Ravi Shanker, on Wednesday, said: “We requested the Central government to withdraw the ESZ notification as we already have the Bhagirathi River Valley Development Authority in Uttarkashi district constituted in the year 2005 that serves the purpose of the ESZ notification, which is that of maintaining ecological balance and sustainable development.”
Mr. Ravi Shanker said that in response to the State’s request, Mr. Misra has asked the Environment Ministry to reconsider the notification.
The delegation also raised the issues of stalled hydroelectric power projects in the State. “We stated the environmental issues around hydroelectric power projects that are obstructing the development of the State. Almost all under-construction hydro-power projects in the State are stalled, at present,” Mr. Ravi Shanker said.
Scientists stamp black-headed squirrel monkeys as rare species
The black-headed squirrel monkey is a distinct species found in South America, say scientists
A study has resolved a long-standing dispute concerning a small number of black-headed squirrel monkeys (Saimiri vanzolinii), which are found only in an isolated part of Brazil.
Whether the monkeys are a sub-species of another species or a species by itself was the point of dispute among scientists.
By its resolution hangs the tale of their uniqueness as primates and the need to preserve their smallest habitat in Brazil threatened by global warming.
The scientists from the University of California — Los Angeles (UCLA) in the US and six other countries used genetic and statistical analysis to find that this group of monkeys split from its sister group, called Saimiri ustus, about 500,000 years ago.
It formed a group called Saimiri boliviensis approximately 1.3 million years ago. Researchers previously had thought that Saimiri boliviensis and Saimiri vanzolinii were the same species.
“We found strong evidence that it is a distinct, separate species. It’s its own unique group,” said study co—author Jessica Lynch Alfaro, adjunct assistant professor in department of anthropology at UCLA. This understanding is particularly significant because the monkeys’ survival is being threatened by climate change.
“They may lose all of their habitat. This species has the smallest, most restricted habitat of any Amazonian primate, and it has been predicted that the habitat may be drastically altered due to changes in weather patterns as a result of global warming,” Alfaro added. The findings could be particularly important in shaping efforts to conserve the biodiversity of primates in South America, the authors said.
Periyar tiger reserve wins NTCA award
For involving local people in managing the habitat
The Periyar Tiger Reserve, spread over 925 sq.km. in Kerala, bagged the National Tiger Conservation Authority (NTCA) biennial award on Tuesday for encouraging local public participation in managing the reserve.
There are 75 communities living around the reserve, including tribal people who are dependent on eco-development programmes, said field director of the reserve Amit Mallick on Tuesday. The reserve set up the Periyar Foundation in 2006 which was a model for other reserves in biodiversity conservation and community participation in managing natural resources.
After this, the Wildlife Protection Act was amended so that each reserve would set up a Foundation, he told The Hindu. Earlier, the India Eco-Development project (IEDP), which was started in the reserve in December 1996, continued up to June 2004. The community-based eco-tourism activities helped visitors and there were night scouting programmes with the help of expert trackers as well. Tourism was supplemented by pepper growing and marketing which was a value addition.
Now self-help groups were involved in honey processing and other income-generating activities, Dr. Mallick said. Of the 75 eco development committees, 15 were tribal and each had about 150 to 200 members. There were 19 different eco-tourism programmes apart from village eco-development programmes like bee-keeping.
The committees also played a major role during the Sabarimala pilgrimage which involved a 23-km trek in the dense forests. Small shops were set up along the way and people helped in regulating the pilgrims and in waste management, removing 40 to 50 tonnes each season.
