Newsdesk
New antibiotic development hailed as game changing A new technique for development of antibiotics could eventually result in many new molecules being taken forward into clinical trials. Tony Kirby reports. The growing crisis of resistance developing to existing antibiotics and the fact that no new classes of antibiotics have been approved since the 1980s is no secret. In the past 5 years, more and more media reports featuring health leaders and even Prime Ministers and Presidents have warned of a potential antibiotic apocalypse, whereby our existing arsenal of drugs becomes so ineffective that we will return to a preantibiotic era in which infections once lethal, but currently under control, could kill again. Despite this increasing panic, progress towards actual new antibiotics that can be released on the market has been slow. However, some hope has arrived in the form a new study published on Jan 22, 2015. In this study, scientists from Northeastern University, Massachusetts, USA, detailed a new technique for growing potential antimicrobials from soil, the source of most existing antibiotics. The team, working with the pharmaceutical company Novobiotic, Massachusetts, USA, created a multichannel device, called an iChip, that allows soil bacteria to be cultured in their natural environment, leading to production of various promising molecules. The most promising of the 25 or so molecules produced so far is one named teixobactin, which has strong activity against Grampositive bacteria such as meticillinresistant Staphylococcus aureus and Mycobacterium tuberculosis. “We need to complete preclinical de velopment, which is a further 2 years, involving more animal model and toxicity testing, and also work on issues around production”, says lead researcher Kim Lewis, director of Northeastern University’s Antimicrobial Discovery Center. www.thelancet.com/infection Vol 15 March 2015
Teixobactin targets lipids that are key components of the bacterial cell wall, and Lewis describes teixobactin as having evolved to avoid resistance. Unfortunately, this new antibiotic does not show activity against Gramnegative bacteria such as Escherichia coli, limiting its potential usefulness. “This is a good paper showing proof of principle”, says Laura Piddock, Professor of Microbiology and Deputy Director of the Institute of Microbiology and Infection at the University of Birmingham, Birmingham, UK. “Although teixobactin has no activity for E coli, the approaches taken by Lewis and colleagues can be extrapolated and used by others; this work opens the door on a new era of natural product antimicrobial discovery.” “There are two significant things about this feat”, says Francis Collins, director of the US National Institutes of Health (NIH), Maryland, USA. “The first is that the new antibiotic not only has the ability to kill a wide range of infection-causing bacteria, but to kill them in a way that may greatly reduce the problem of resistance. The second is that researchers identified teixobactin using an ingenious approach that enhances our ability to search one of nature’s richest sources of potential antibiotics—soil. However, over the past few decades, scouring the soil for new antibiotics has proven to be extremely difficult because the vast majority of dirtdwelling microbes can’t be grown under traditional microbiological conditions in the laboratory.” Collins also stresses teixobactin’s absence of activity against Gram-negative bacteria, “which include the deadly and rapidly emerging threat of klebsiella and other carbapenem-resistant Enterobacteriaceae”.
In the past 3 years, the EU’s Innovative Medicines Initiative (IMI) has announced its “New Drugs 4 Bad Bugs” programme (ND4BB). IMI is Europe’s largest public–private partnership, linking the pharmaceutical industry with leading academic centres, and is gradually establishing networks that will eventually test new antimicrobials. “The IMI antibiotic resistance programme is about much more than clinical development of antibiotics”, says Irene Norstedt, IMI Acting Executive Director. “It covers everything from the basic science of antibiotic resistance, including how to get antibiotics into the bacteria in the first place, through the early stages of drug discovery and development, to clinical trials and the creation of a pan-European clinical trial network.” She adds that “it is now clear to most stakeholders in drug development, including industry and academia, that the really big challenges, like antimicrobial resistance, can only be tackled by collaboration between all stakeholders. At the same time, IMI’s successes—including in fields beyond infectious disease—amply demonstrate the success and added value of a collaborative approach”. However the IMI programme is not just about finding new ways to tackle antibiotic resistance, but also finding new ways to avoid it. Within the ND4BB programme is the Combating Bacterial Resistance in Europe (COMBACTE) consortium, and one objective of this consortium is to support clinical development of a monoclonal antibody developed by MedImmune, Maryland, USA. This molecule, MEDI4893, targets a toxin produced by S aureus, which is one of the leading bacteria often associated with hospital-associated infections and linked to resistance issues. A
For the teixobactin study see Nature 2015; 517: 455–59 For the blog on new antibiotics by NIH Director Francis Collins see http://directorsblog.nih. gov/2015/01/13/digging-upnew-antibiotics For more on the Innovative Medicines Initiative see http:// www.imi.europa.eu For more on the COMBACTE consortium see http://www. combacte.com
271
Newsdesk
phase 2 trial of MEDI4893, named SAATELLITE, has just enrolled its first patient. Led by Hasan Jafri from MedImmune and Bruno François from Limoges University Hospital, Limoges, France, this trial also represents a shift in thinking in the infectious disease discipline. This study uses a preemptive approach with a monoclonal antibody to help prevent ventilatorassisted and nosocomial pneumonia due to S aureus. 462 patients are expected to be enrolled in this study across roughly 80 sites in Europe. The US NIH has various other projects to drive forward antimicrobial innovation; for example, they have awarded a separate grant to help discovery of new antimicrobials specific to Clostridium difficile, but with the same technology used to discover teixobactin. Other projects include use of computer technology to design a new drug, use of basic chemistry to understand how a
powerful antibiotic substance is made in nature, and rediscovery of natural products through analysis of marine sponges. The US NIH also has contracts with companies to develop new antibiotics or drugs to be used in conjunction with antibiotics. For example, they are working with the company Aridis, California, USA, which is developing inhaled gallium citrate, an elemental antimicrobial to treat bacterial pneumonia. Elsewhere, they are working with another company, VenatoRx, Philadelphia, USA, which is developing a β-lactamase inhibitor to rescue the activity of existing antibiotics to treat bacterial infections expressing the range of known β-lactams. Asked whether countries and international agencies are finally taking the threat of antibiotic resistance seriously, Piddock says that “it is now recognised at the highest levels that the antibiotic resistance is a global crisis. However,
whilst there is agreement on this issue, there is not agreement on the best way to tackle it. This is probably because this will need to be addressed in many different ways in many different countries”. She concludes that “the new tool, the iChip, allowed isolation of teixobactin from a soil microorganism that microbiologists had been unable to grow in the test tube. This screening could be a game changer for discovering new antibiotics as it allows compounds to be isolated from microorganisms in the soil that do not grow under normal laboratory conditions. Therefore, the iChip can now be applied to find natural antibiotics produced by microorganisms from other environmental sources—and, maybe, one of these will be active against bacteria such as E coli and can be made into a drug for patients”.
Tony Kirby
Infectious diseases surveillance update For more on Guillain-Barre syndrome in Ireland see http:// promedmail.org/direct. php?id=3138374 For more on measles in the USA see http://www.cdc.gov/ measles/multi-state-outbreak. html For more on MERS-CoV in Saudi Arabia see http://promedmail. org/direct.php?id=3148681 For more on dengue in Malaysia see http://www.therakyatpost. com/news/2015/02/05/6000dengue-cases-recorded-selangorlast-month/#ixzz3RBBwJTb2
GBS in Ireland As of Feb 3, 2015, six cases of GuillainBarré syndrome (GBS) were reported from Duleek, County Meath, Ireland; four cases have been confirmed and two are suspected. With a population of fewer than 6000 residents, Duleek should only have a 0·00001% chance of six people contracting the disease. The cause of the suspected cluster of the disease remains unknown; however, both the Health Service Executive and the Environmental Protection Agency are investigating the cause. Most confirmed cases of GBS are linked to a previous episode of infection, a vaccination, or a surgical intervention. Since 2010, cases in Duleek have been linked to an environmental issue.
Measles in the USA Between Dec 28, 2014, and Feb 6, 2015, 114 cases of measles have been linked to an initial exposure at Disneyland 272
or Disney California Adventure Park in Anaheim, California. Cases in this continuing outbreak have been reported from seven states in the USA, with 99 of the cases from California. Officials suspect that the outbreak is likely to have started with a traveller who visited the amusement park while infectious. Multistate investigations into this outbreak are continuing and more cases are expected.
MERS-CoV in Saudi Arabia Ten new cases of Middle East respiratory syndrome coronavirus (MERS-CoV), including one fatality, were reported to the Saudi Arabia Ministry of Health between Feb 3 and Feb 6, 2015. Two of the sufferers had a history of contact with animals in the 14 days preceding onset of illness. These cases have brought the total reported cases in Saudi Arabia to 42 for the year so far; the case fatality rate
is roughly 43%. The source of MERSCoV infection and the method of transmission have not been identified.
Dengue in Malaysia 6686 cases of the mosquito-borne dengue virus infection have been reported for January in the state of Selangor, Malaysia. For the same period in 2014, 3813 cases were reported. Mortality has also increased as 17 people have so far died from their illness, whereas two fatalities were reported for the same period last year. 48% of the reported cases are from the Petaling district where special control programmes are to be implemented because cases have reached a critical level. These programmes will aim to disrupt breeding sites for the Aedes aegypti mosquito vector that transmits the virus.
Ruth Zwizwai www.thelancet.com/infection Vol 15 March 2015
New antibiotic development hailed as game changing A new technique for development of antibiotics could eventually result in many new molecules being taken forward into clinical trials. Tony Kirby reports. The growing crisis of resistance developing to existing antibiotics and the fact that no new classes of antibiotics have been approved since the 1980s is no secret. In the past 5 years, more and more media reports featuring health leaders and even Prime Ministers and Presidents have warned of a potential antibiotic apocalypse, whereby our existing arsenal of drugs becomes so ineffective that we will return to a preantibiotic era in which infections once lethal, but currently under control, could kill again. Despite this increasing panic, progress towards actual new antibiotics that can be released on the market has been slow. However, some hope has arrived in the form a new study published on Jan 22, 2015. In this study, scientists from Northeastern University, Massachusetts, USA, detailed a new technique for growing potential antimicrobials from soil, the source of most existing antibiotics. The team, working with the pharmaceutical company Novobiotic, Massachusetts, USA, created a multichannel device, called an iChip, that allows soil bacteria to be cultured in their natural environment, leading to production of various promising molecules. The most promising of the 25 or so molecules produced so far is one named teixobactin, which has strong activity against Grampositive bacteria such as meticillinresistant Staphylococcus aureus and Mycobacterium tuberculosis. “We need to complete preclinical de velopment, which is a further 2 years, involving more animal model and toxicity testing, and also work on issues around production”, says lead researcher Kim Lewis, director of Northeastern University’s Antimicrobial Discovery Center. www.thelancet.com/infection Vol 15 March 2015
Teixobactin targets lipids that are key components of the bacterial cell wall, and Lewis describes teixobactin as having evolved to avoid resistance. Unfortunately, this new antibiotic does not show activity against Gramnegative bacteria such as Escherichia coli, limiting its potential usefulness. “This is a good paper showing proof of principle”, says Laura Piddock, Professor of Microbiology and Deputy Director of the Institute of Microbiology and Infection at the University of Birmingham, Birmingham, UK. “Although teixobactin has no activity for E coli, the approaches taken by Lewis and colleagues can be extrapolated and used by others; this work opens the door on a new era of natural product antimicrobial discovery.” “There are two significant things about this feat”, says Francis Collins, director of the US National Institutes of Health (NIH), Maryland, USA. “The first is that the new antibiotic not only has the ability to kill a wide range of infection-causing bacteria, but to kill them in a way that may greatly reduce the problem of resistance. The second is that researchers identified teixobactin using an ingenious approach that enhances our ability to search one of nature’s richest sources of potential antibiotics—soil. However, over the past few decades, scouring the soil for new antibiotics has proven to be extremely difficult because the vast majority of dirtdwelling microbes can’t be grown under traditional microbiological conditions in the laboratory.” Collins also stresses teixobactin’s absence of activity against Gram-negative bacteria, “which include the deadly and rapidly emerging threat of klebsiella and other carbapenem-resistant Enterobacteriaceae”.
In the past 3 years, the EU’s Innovative Medicines Initiative (IMI) has announced its “New Drugs 4 Bad Bugs” programme (ND4BB). IMI is Europe’s largest public–private partnership, linking the pharmaceutical industry with leading academic centres, and is gradually establishing networks that will eventually test new antimicrobials. “The IMI antibiotic resistance programme is about much more than clinical development of antibiotics”, says Irene Norstedt, IMI Acting Executive Director. “It covers everything from the basic science of antibiotic resistance, including how to get antibiotics into the bacteria in the first place, through the early stages of drug discovery and development, to clinical trials and the creation of a pan-European clinical trial network.” She adds that “it is now clear to most stakeholders in drug development, including industry and academia, that the really big challenges, like antimicrobial resistance, can only be tackled by collaboration between all stakeholders. At the same time, IMI’s successes—including in fields beyond infectious disease—amply demonstrate the success and added value of a collaborative approach”. However the IMI programme is not just about finding new ways to tackle antibiotic resistance, but also finding new ways to avoid it. Within the ND4BB programme is the Combating Bacterial Resistance in Europe (COMBACTE) consortium, and one objective of this consortium is to support clinical development of a monoclonal antibody developed by MedImmune, Maryland, USA. This molecule, MEDI4893, targets a toxin produced by S aureus, which is one of the leading bacteria often associated with hospital-associated infections and linked to resistance issues. A
For the teixobactin study see Nature 2015; 517: 455–59 For the blog on new antibiotics by NIH Director Francis Collins see http://directorsblog.nih. gov/2015/01/13/digging-upnew-antibiotics For more on the Innovative Medicines Initiative see http:// www.imi.europa.eu For more on the COMBACTE consortium see http://www. combacte.com
271
Newsdesk
phase 2 trial of MEDI4893, named SAATELLITE, has just enrolled its first patient. Led by Hasan Jafri from MedImmune and Bruno François from Limoges University Hospital, Limoges, France, this trial also represents a shift in thinking in the infectious disease discipline. This study uses a preemptive approach with a monoclonal antibody to help prevent ventilatorassisted and nosocomial pneumonia due to S aureus. 462 patients are expected to be enrolled in this study across roughly 80 sites in Europe. The US NIH has various other projects to drive forward antimicrobial innovation; for example, they have awarded a separate grant to help discovery of new antimicrobials specific to Clostridium difficile, but with the same technology used to discover teixobactin. Other projects include use of computer technology to design a new drug, use of basic chemistry to understand how a
powerful antibiotic substance is made in nature, and rediscovery of natural products through analysis of marine sponges. The US NIH also has contracts with companies to develop new antibiotics or drugs to be used in conjunction with antibiotics. For example, they are working with the company Aridis, California, USA, which is developing inhaled gallium citrate, an elemental antimicrobial to treat bacterial pneumonia. Elsewhere, they are working with another company, VenatoRx, Philadelphia, USA, which is developing a β-lactamase inhibitor to rescue the activity of existing antibiotics to treat bacterial infections expressing the range of known β-lactams. Asked whether countries and international agencies are finally taking the threat of antibiotic resistance seriously, Piddock says that “it is now recognised at the highest levels that the antibiotic resistance is a global crisis. However,
whilst there is agreement on this issue, there is not agreement on the best way to tackle it. This is probably because this will need to be addressed in many different ways in many different countries”. She concludes that “the new tool, the iChip, allowed isolation of teixobactin from a soil microorganism that microbiologists had been unable to grow in the test tube. This screening could be a game changer for discovering new antibiotics as it allows compounds to be isolated from microorganisms in the soil that do not grow under normal laboratory conditions. Therefore, the iChip can now be applied to find natural antibiotics produced by microorganisms from other environmental sources—and, maybe, one of these will be active against bacteria such as E coli and can be made into a drug for patients”.
Tony Kirby
Infectious diseases surveillance update For more on Guillain-Barre syndrome in Ireland see http:// promedmail.org/direct. php?id=3138374 For more on measles in the USA see http://www.cdc.gov/ measles/multi-state-outbreak. html For more on MERS-CoV in Saudi Arabia see http://promedmail. org/direct.php?id=3148681 For more on dengue in Malaysia see http://www.therakyatpost. com/news/2015/02/05/6000dengue-cases-recorded-selangorlast-month/#ixzz3RBBwJTb2
GBS in Ireland As of Feb 3, 2015, six cases of GuillainBarré syndrome (GBS) were reported from Duleek, County Meath, Ireland; four cases have been confirmed and two are suspected. With a population of fewer than 6000 residents, Duleek should only have a 0·00001% chance of six people contracting the disease. The cause of the suspected cluster of the disease remains unknown; however, both the Health Service Executive and the Environmental Protection Agency are investigating the cause. Most confirmed cases of GBS are linked to a previous episode of infection, a vaccination, or a surgical intervention. Since 2010, cases in Duleek have been linked to an environmental issue.
Measles in the USA Between Dec 28, 2014, and Feb 6, 2015, 114 cases of measles have been linked to an initial exposure at Disneyland 272
or Disney California Adventure Park in Anaheim, California. Cases in this continuing outbreak have been reported from seven states in the USA, with 99 of the cases from California. Officials suspect that the outbreak is likely to have started with a traveller who visited the amusement park while infectious. Multistate investigations into this outbreak are continuing and more cases are expected.
MERS-CoV in Saudi Arabia Ten new cases of Middle East respiratory syndrome coronavirus (MERS-CoV), including one fatality, were reported to the Saudi Arabia Ministry of Health between Feb 3 and Feb 6, 2015. Two of the sufferers had a history of contact with animals in the 14 days preceding onset of illness. These cases have brought the total reported cases in Saudi Arabia to 42 for the year so far; the case fatality rate
is roughly 43%. The source of MERSCoV infection and the method of transmission have not been identified.
Dengue in Malaysia 6686 cases of the mosquito-borne dengue virus infection have been reported for January in the state of Selangor, Malaysia. For the same period in 2014, 3813 cases were reported. Mortality has also increased as 17 people have so far died from their illness, whereas two fatalities were reported for the same period last year. 48% of the reported cases are from the Petaling district where special control programmes are to be implemented because cases have reached a critical level. These programmes will aim to disrupt breeding sites for the Aedes aegypti mosquito vector that transmits the virus.
Ruth Zwizwai www.thelancet.com/infection Vol 15 March 2015
