A new chemical compound developed by a team of scientists at the Jawaharlal Nehru Centre for Advanced Scientific Research in Bengaluru could improve the effectiveness of antibiotics.
Antibiotics are drugs that act against bacteria by killing them, halting their growth or preventing them from performing essential functions. Antibiotics thus make it easier for the body’s immune system to fight the bacteria.
“Most antibiotics do a particular job of killing one aspect of a bacterial cell,” said Jayanta Haldar, assistant professor at the Centre, and the leader of the team. “But instead of targeting individual functions, our compound targets the bacteria’s cell membrane, which is linked to several functions.”
Because this compound obstructs bacteria from mutating, they are less likely to develop a resistance to it than to other antibiotics. While bacteria reproduce every 15 minutes to an hour, antibiotics take a few days to several months to either kill all the infectious bacteria or halt their reproduction.
During each reproductive cycle, some of the bacteria can mutate, and some of them do so in such a way that they become resistant to the antibiotic. By hindering mutation, the compound also lowers chances of the bacteria becoming drug-resistant.
Haldar’s team published its preliminary findings in the Journal of Medicinal Chemistry in May 2014, and has submitted its full findings to other journals. The team has also filed for patents in India, the US, Canada, South Korea, Australia and the European Union.
But Haldar’s compound might take up to 20 years to reach ordinary consumers, if at all it receives funding to take it through several phases of expensive testing and clinical trials with hundreds to thousands of patients. Pharmaceutical companies are often sponsors of the process, but as the US Food and Drug Administration's tests for antibiotics are particularly stringent, there is a high cost and risk for a company that might consider backing a compound.
Yet there is a dire need for new antibiotics, especially ones that reduces the chances of making the bacteria drug-resistant. Because of the stringent testing only a few antibiotics have made it to the market in the past two decades, while existing antibiotics are gradually proving to be ineffective because bacteria are becoming resistant to them.
A study released on July 10 by the Princeton University in the journal The Lancet Infectious Diseases said that there might soon be an urgent need for new kinds of antibiotics that tackle bacteria in innovative ways.
The need for drug-resistant antibiotics is particularly strong in India, where there are high levels of misuse, in the form of people not completing their full course, taking the wrong antibiotics or taking antibiotics for viral infections, all of which increase the chances of bacteria mutating to become drug-resistant.
Carbapenems, a class of antibiotics normally used as a last resort for the most persistent of infections, are among the drugs Indians most frequently misuse, either by not following the prescribed dosage or by having it when not required, said the Princeton study.
If bacteria develop resistance to even these last-resort drugs, then strains of drug-resistant diseases could become rampant, as was the case last year with several reported instances of multi-drug-resistant tuberculosis.
“New antibiotics are always important,” said Tusharkanti Chakraborty, head of the department of organic chemistry at the Indian Institute of Science in Bengaluru. “The situation is now alarming because last-resort drugs are also not working.”
Science of antibiotics
Antibiotics can be classified according to the biochemical functions in the bacteria they attempt to incapacitate: DNA replication, cell wall biosynthesis, folic acid synthesis and protein synthesis.
Most antibiotics target just one function. Erythromycin, for example, which is used to treat bronchitis and diphtheria, halts the last function, protein synthesis. Vancomycin, which is used to treat pneumonia, inhibits cell wall biosynthesis.
When a bacteria mutates, it might, for instance, alter the way it binds protein. The antibiotic that inhibits that particular method of protein synthesis will then be rendered ineffective.
One class of antibiotics that tries to hinder cell-wall biosynthesis, called glycopeptides, of which vancomycin is one, is normally used as a drug of last resort for patients who do not respond to other treatment because they have been infected with multi-drug resistant bacteria.
But there are bacteria that have developed resistance to even this class of drugs. The compound that Haldar and his team have developed is an improved derivative of vancomycin that both inhibits cell wall biosynthesis and disrupts the bacterial cell membrane.
The cell membrane, located within the cell wall, is linked to several integral functions in a bacterial cell, which is why when it is destroyed, bacteria are unable to reproduce or function effectively. Most significantly, bacteria seem to lose their ability to mutate and therefore their ability to develop a resistance to antibiotics. If bacteria cannot develop resistance to this drug, the drug will be effective for far longer.
Haldar’s compound is not the only one that works against the cell membrane. Two other antibiotic compounds, also vancomycin derivatives, Telavancin and Oritavancin, perform similar functions. Oritavancin is yet to be registered with the FDA. While Telavancin was approved in 2009, it is highly toxic and has a high risk of causing kidney failure, which is why it is used only as a last resort.
Haldar’s compound, said Lynn Silver, a scientific consultant at LL Silver Consulting based in the US in an email reply to Scroll.in based on his published paper, hit structures such as the cell wall and membranes, and not functions. Therefore, bacteria cannot directly mutate to resist it. Rapid resistance will also not result when compounds have multiple targets that are produced by multiple genes, she added.
“At least in the short term, I do think it would take a long time to get resistance to this compound,” she said.
Lab to market
The road from Haldar's lab to our medicine chests may be long and tortuous.
There might be chemicals that are promising at the research stage, but don't find big company funding to take them to the next level of testing.
But Silver said there were problems with the science too. “It is easy to find things that kill bacteria, but the hurdle is to prove that they are safe. Money and financial considerations are very important, but the main problems are scientific. Indeed, resistance and toxicity are main problems. That's why things don't make it past testing.”
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Antibiotics are drugs that act against bacteria by killing them, halting their growth or preventing them from performing essential functions. Antibiotics thus make it easier for the body’s immune system to fight the bacteria.
“Most antibiotics do a particular job of killing one aspect of a bacterial cell,” said Jayanta Haldar, assistant professor at the Centre, and the leader of the team. “But instead of targeting individual functions, our compound targets the bacteria’s cell membrane, which is linked to several functions.”
Because this compound obstructs bacteria from mutating, they are less likely to develop a resistance to it than to other antibiotics. While bacteria reproduce every 15 minutes to an hour, antibiotics take a few days to several months to either kill all the infectious bacteria or halt their reproduction.
During each reproductive cycle, some of the bacteria can mutate, and some of them do so in such a way that they become resistant to the antibiotic. By hindering mutation, the compound also lowers chances of the bacteria becoming drug-resistant.
Haldar’s team published its preliminary findings in the Journal of Medicinal Chemistry in May 2014, and has submitted its full findings to other journals. The team has also filed for patents in India, the US, Canada, South Korea, Australia and the European Union.
But Haldar’s compound might take up to 20 years to reach ordinary consumers, if at all it receives funding to take it through several phases of expensive testing and clinical trials with hundreds to thousands of patients. Pharmaceutical companies are often sponsors of the process, but as the US Food and Drug Administration's tests for antibiotics are particularly stringent, there is a high cost and risk for a company that might consider backing a compound.
Yet there is a dire need for new antibiotics, especially ones that reduces the chances of making the bacteria drug-resistant. Because of the stringent testing only a few antibiotics have made it to the market in the past two decades, while existing antibiotics are gradually proving to be ineffective because bacteria are becoming resistant to them.
A study released on July 10 by the Princeton University in the journal The Lancet Infectious Diseases said that there might soon be an urgent need for new kinds of antibiotics that tackle bacteria in innovative ways.
The need for drug-resistant antibiotics is particularly strong in India, where there are high levels of misuse, in the form of people not completing their full course, taking the wrong antibiotics or taking antibiotics for viral infections, all of which increase the chances of bacteria mutating to become drug-resistant.
Carbapenems, a class of antibiotics normally used as a last resort for the most persistent of infections, are among the drugs Indians most frequently misuse, either by not following the prescribed dosage or by having it when not required, said the Princeton study.
If bacteria develop resistance to even these last-resort drugs, then strains of drug-resistant diseases could become rampant, as was the case last year with several reported instances of multi-drug-resistant tuberculosis.
“New antibiotics are always important,” said Tusharkanti Chakraborty, head of the department of organic chemistry at the Indian Institute of Science in Bengaluru. “The situation is now alarming because last-resort drugs are also not working.”
Science of antibiotics
Antibiotics can be classified according to the biochemical functions in the bacteria they attempt to incapacitate: DNA replication, cell wall biosynthesis, folic acid synthesis and protein synthesis.
Most antibiotics target just one function. Erythromycin, for example, which is used to treat bronchitis and diphtheria, halts the last function, protein synthesis. Vancomycin, which is used to treat pneumonia, inhibits cell wall biosynthesis.
When a bacteria mutates, it might, for instance, alter the way it binds protein. The antibiotic that inhibits that particular method of protein synthesis will then be rendered ineffective.
One class of antibiotics that tries to hinder cell-wall biosynthesis, called glycopeptides, of which vancomycin is one, is normally used as a drug of last resort for patients who do not respond to other treatment because they have been infected with multi-drug resistant bacteria.
But there are bacteria that have developed resistance to even this class of drugs. The compound that Haldar and his team have developed is an improved derivative of vancomycin that both inhibits cell wall biosynthesis and disrupts the bacterial cell membrane.
The cell membrane, located within the cell wall, is linked to several integral functions in a bacterial cell, which is why when it is destroyed, bacteria are unable to reproduce or function effectively. Most significantly, bacteria seem to lose their ability to mutate and therefore their ability to develop a resistance to antibiotics. If bacteria cannot develop resistance to this drug, the drug will be effective for far longer.
Haldar’s compound is not the only one that works against the cell membrane. Two other antibiotic compounds, also vancomycin derivatives, Telavancin and Oritavancin, perform similar functions. Oritavancin is yet to be registered with the FDA. While Telavancin was approved in 2009, it is highly toxic and has a high risk of causing kidney failure, which is why it is used only as a last resort.
Haldar’s compound, said Lynn Silver, a scientific consultant at LL Silver Consulting based in the US in an email reply to Scroll.in based on his published paper, hit structures such as the cell wall and membranes, and not functions. Therefore, bacteria cannot directly mutate to resist it. Rapid resistance will also not result when compounds have multiple targets that are produced by multiple genes, she added.
“At least in the short term, I do think it would take a long time to get resistance to this compound,” she said.
Lab to market
The road from Haldar's lab to our medicine chests may be long and tortuous.
There might be chemicals that are promising at the research stage, but don't find big company funding to take them to the next level of testing.
But Silver said there were problems with the science too. “It is easy to find things that kill bacteria, but the hurdle is to prove that they are safe. Money and financial considerations are very important, but the main problems are scientific. Indeed, resistance and toxicity are main problems. That's why things don't make it past testing.”