New drug candidate targeting bacterial metabolism could cut TB treatment time
The findings, published in Nature magazine recently, are the result of a collaborative effort between researchers at Johnson & Johnson and the London School of Hygiene & Tropical Medicine (LSHTM).
JNJ-6640 works by inhibiting the enzyme PurF, which deprives the TB bacterium of essential metabolites, ultimately leading to bacterial death.
Anil Koul, professor of translational discovery at LSHTM and lead corresponding author of the study, pointed out that the over-70,000-year-old human pathogen had evolved into a highly persistent organism. 'Its ability to survive inside macrophages, resist antibiotics and adapt to hostile environments makes TB extremely difficult to eliminate,' he said, noting that TB remains the leading infectious cause of death globally and infects nearly a quarter of the world's population.
Unlike most current TB drugs which target actively replicating bacteria, JNJ-6640 showed bactericidal activity against both replicating and dormant TB populations. It remained effective under multiple stress-induced dormancy models, including nutrient deprivation, hypoxia (low-oxygen conditions) and intracellular infection. This is particularly relevant, as TB bacilli often persist in non-replicating states within granulomas (clusters of immune cells that wall off the infection), where they are shielded from antibiotics.
'Many frontline TB drugs, such as isoniazid, lose efficacy in these dormant or low-oxygen conditions,' said Koul. 'JNJ-6640 retained activity in all these conditions. This broad-spectrum activity suggests that the drug candidate could contribute to treatment shortening, an essential goal in TB therapy.'
Preclinical studies also indicate that JNJ-6640 may have potential in treating drug-resistant TB. It demonstrated no cross-resistance with existing drugs and was effective in combination with bedaquiline and pretomanid—two key components of newer regimens for multidrug-resistant TB. 'Replacing current drugs like linezolid, which carries significant toxicity risks, or moxifloxacin, which is increasingly compromised by resistance, is crucial. JNJ-6640's new mechanism and safety potential make it a strong candidate for future combination regimens,' said Koul.
In addition to its bactericidal activity, JNJ-6640 exhibited a post-antibiotic effect (continued killing of bacteria even after the drug is removed) in vitro. While this property could help reduce relapse rates and improve patient recovery, researchers are cautious in interpreting its long-term clinical relevance. 'We need more data to determine whether this effect will translate into reduced relapse or allow intermittent dosing in patients,' he said.
One limitation of JNJ-6640 is its poor metabolic stability (it is broken down too quickly to be effective when given orally) in mice. To overcome this, the team developed a long-acting injectable (LAI) formulation. 'The goal remains to develop an orally bioavailable molecule, but the LAI formulation allowed us to maintain therapeutic concentrations in vivo and validate the drug candidate's potential. LAIs could also be useful for prophylactic therapy in high-risk individuals or those with poor adherence,' said Koul. At present, JNJ-6640 is considered a validated lead drug candidate but not yet suitable for clinical trials.
Koul emphasised that the discovery of JNJ-6640 exemplifies the importance of academic-industry collaboration in addressing unmet medical needs. 'This project brought together experts in microbiology, structural biology, chemistry and pharmacology,' he said. 'Targeting novel bacterial pathways is not only feasible—it's essential. We urgently need global funders and policymakers to prioritise TB drug development if we are to control, and eventually eliminate, this disease.'
Try Our AI Features
Explore what Daily8 AI can do for you:
Comments
No comments yet...
Related Articles
The Print
13 hours ago
- The Print
Puducherry adopts verbal autopsy model to identify TB treatment delay patterns
'Using this method, doctors at IGMC&RI, Puducherry, are investigating the causes behind deaths due to tuberculosis and identifying both patient-related and health system related factors,' Dr Kavita Vasudevan from the Community Medicine Department at Medical college, who is leading the project, said. The Indira Gandhi Medical College and Research Institute (IGMC&RI) in Puducherry has undertaken the task of analysing 160 TB deaths that had been reported in the UT in 2024 and would be submitting its finding to the Centre's TB division,' State TB Officer of Puducherry, Dr C Venkatesh told PTI. New Delhi, Jul 8 (PTI) Puducherry has adopted the verbal autopsy model to assess reasons behind tuberculosis deaths, identify patterns for treatment delay, improve triaging process and referral mechanism. A verbal autopsy is an interview-based process where close relatives or caregivers of the deceased are asked questions about circumstances and factors leading to death. For example, they are asked about the deceased's symptoms, treatment history, hospital admission time, treatment received and the circumstances at the time of death. This information is collected in a structured format, after which doctors assess the probable cause of death. This technique involves mixing both quantitative and qualitative methods to arrive at factors that lead to mortality in TB patients. For quantitative method, clinical records of TB deaths are being reviewed, while for the qualitative component, stakeholder interviews are being conducted with National TB Elimination Programme (NTEP) staff as well as the kin of the deceased patients, Dr Vasudevan explained. Preliminary analysis has revealed that the majority of TB deaths are occurring within seven days of being diagnosed, implying there is a delay in patients accessing the health facility and reaching the hospital late, she said. 'A significant number of patients who died belong to the neighbouring districts of Tamil Nadu. These patients have come to health facilities in Puducherry for availing treatment and often give false addresses or addresses of their relatives in Puducherry,' she said. Social factors also play a role and in some cases, social stigma related to TB or family neglect prevented patients from seeking timely treatment, Dr Vasudevan explained. Verbal autopsy is an important tool for public health, especially when the cause of death and the factors leading to death cannot be clearly determined from medical records. Puducherry's health department is reportedly planning to make verbal autopsies mandatory for every TB death case, Dr Venkatesh informed. Identifying the reasons for TB mortality can provide critical insights into the factors leading to these deaths, he said. In addition, the differentiated TB care approach recommended by the Central TB division is also implemented in Puducherry. This approach involves the provision of comprehensive evaluation and supportive treatment services at various healthcare levels. By employing this risk stratification process, healthcare providers can tailor their approach to ensure appropriate care for individuals identified with specific risks, he said. The World Health Organisation (WHO) has also advised use of verbal autopsies as an important tool in the fight against TB to better understand early symptoms, symptom duration, treatment initiation and interruptions, and the diagnostic process. Verbal autopsy provides insights into patient as well as health system delays, social or financial challenges faced during illness, perceptions of healthcare services and barriers to accessing timely diagnosis and treatment. Tuberculosis is one of the top ten causes of death worldwide and the second leading cause of death from a single infectious agent after coronavirus disease, surpassing HIV. India's TB burden remains a major public health challenge, highlighted Dr Vasudevan. According to recent estimates, number of deaths due to TB in India was 23 per lakh population. In Puducherry, the total TB notifications for the year 2022 was 3,835 which translates to nearly 247 TB notifications per one lakh population with a death rate of eight per cent, she said. As part of the Nationals Strategic plan and WHO End TB Strategy, one of the milestones is to reduce global TB deaths by 90 per cent by 2025, using 2015 as the baseline, she stated. A comprehensive approach is essential to effectively tackle TB, which includes provision of quality TB care through access to quality diagnostics, effective drugs for therapy, prevention strategies and identifying the underlying causes of mortality associated with the disease. PTI PLB DV DV This report is auto-generated from PTI news service. ThePrint holds no responsibility for its content.
Time of India
15 hours ago
- Time of India
Covid-19 claims 2 more lives in Indore; toll rises to 8
INDORE: COVID-19 continues to spread its deadly reach in Indore, with the city reporting two fatalities in as many days – a 55-year-old woman and a 64-year-old woman. These unfortunate deaths bring the total number of COVID-related fatalities in Madhya Pradesh to eight. According to Dr Nirmala Akhand, IDSP Nodal Officer, the 64-year-old woman's death was reported on Sunday. "She was suffering from multiple underlying conditions, including Type 1 respiratory failure, septicemia, septic shock, and viral pneumonia," Dr Akhand stated. She further confirmed that the 55-year-old woman passed away from COVID-19 on Monday. "She had a history of TB and other comorbidities," Dr Akhand added. "With these two cases, the total number of COVID-related deaths reported specifically in Indore has now risen to three." The latest two deaths in Indore contribute to the overall increase in COVID-19 related fatalities across Madhya Pradesh, bringing the state's total to eight. Previous victims included a 44-year-old woman from Khargone, a 74-year-old woman also from Indore, a 52-year-old TB patient from Ratlam, and a 52-year-old woman from Bhind. In terms of new infections, Indore reported one new COVID-19 case on Monday. This brings the district's cumulative total to 187, with 12 active cases currently. All active patients are reportedly under home isolation.
The Print
18 hours ago
- The Print
Bringing dramatic drop in TB deaths, how TN set an example for rest of India with one-of-a-kind model
While TB-related death simply refers to a death among a person with TB within 12 months of notification (diagnosis), early TB death refers to deaths that happen within two months, often within the first few weeks of the notification. It is estimated that around 70 percent of TB deaths in the state are early TB deaths. An analysis by the agencies implementing the Tamil Nadu Kasanoi Erappila Thittam (TN-KET, which means TB death-free project) has shown that within six months of the launch of the initiative in April 2022, overall TB-related deaths have come down by nearly 10 percent while early TB fatalities reduced by nearly 20 percent. Chennai: A first-of-its-kind statewide differentiated tuberculosis (TB) care initiative in Tamil Nadu has significantly brought down TB deaths in the state, prompting researchers to pitch it as a model that can be replicated across the country. These results from TN-KET hold significance for India which continues to report the highest burden of TB and TB-related mortalities globally despite making significant strides in curbing the burden of the bacterial disease over the last several years. India is considered a TB endemic country, a highly infectious disease caused by a bacteria called Bacillus Mycobacterium Tuberculosis, which is spread when people who are sick with TB expel the pathogen into the air, mostly by coughing. Spearheaded by the Tamil Nadu State TB Cell and Indian Council of Medical Research-National Institute of Epidemiology (ICMR-NIE), the TN-KET initiative involves triaging (preliminary assessment) adults with TB at diagnosis, and those identified as severely ill based on specified indicators are prioritised immediately for referral, comprehensive assessment, and inpatient care. 'The key aim is to gauge or predict the patients who are likely to die due to the infectious disease while first identifying the disease in them and immediately offer them hospitalised care to treat the severe symptoms they have,' said ICMR-NIE director Dr Manoj Murhekar. The initiative, also supported by the World Health Organisation (WHO) India and the ICMR National Institute for Research in TB (ICMR-NIRT), has been implemented in all 38 districts of Tamil Nadu, except for Chennai. 'This initiative has shown that it is possible to bring down TB-related deaths remarkably by following some scientifically designed tools and methods. Severe illness can be quickly identified through triaging and they can be promptly admitted after diagnosis,' Dr Hemant Deepak Shewade, a senior medical scientist with ICMR-NIE who is associated with the initiative, told ThePrint. While the impact of the project in the first year has been analysed, the analysis of the second year (2023-24) is still underway but the early indications from routine monitoring of TN-KET suggest that it is even better than the previous results, Shewade said. 'We feel that scaling the model across India will be beneficial in bringing down the number of people dying every year due to the disease,' he added. The senior scientist, however, cautioned that such an initiative could only bring down TB-related deaths by up to 30 percent, and measures like detecting all TB incidents, early detection, comorbidity management, universal health coverage, among others, were crucial to further reduce TB deaths in the country. Dr Asha Frederick, Tamil Nadu's State TB Officer, said that district TB officers and Nodal physicians have played a key role in the implementation of the initiative. 'We recommend that these triage variables are captured elsewhere including other Indian states and high TB burden countries to guide patient management,' Dr Frederick said. On the future plans for the TN-KET, the state has started identifying other severe comorbidities like uncontrolled Diabetes (requiring insulin) among people with TB. 'If this goes well, we plan to cover other severe comorbidities like severe addiction to alcohol and tobacco,' Frederick added. According to the World TB report 2024 by the WHO, there were an estimated 28 lakh incident people with TB in 2023, 26 percent of global TB burden. Also, the country had an estimated 3.1 lakh TB deaths that year which was 29 percent of all TB mortalities globally. Tamil Nadu is among the states with high TB burden in the country. Also Read: Lancet report highlights gaps in immunisation—no routine vaccine for 14.4 lakh Indian kids in 2023 How the strategy works As part of the project, health workers triage every new TB-diagnosed adult (all above 15 years) for very severe undernutrition, respiratory distress or poor physical condition on five variables—body mass index (BMI), pedal oedema (swelling of feet and ankles), respiratory rate, oxygen saturation, and ability to stand without support. This is carried out as a health system initiative in routine operational settings by existing health workforce. Whether or not a patient is severely ill is confirmed by entering the details into a software application TB SeWA (Severe TB Web Application). All those identified as severely ill are then prioritised for in-patient care by nodal physicians in nodal inpatient care facilities of the districts, using TN-KET case record form and in-patient care guides specifically developed for such patients. A study published on the early implementation of the project and its feasibility underlined that 80-90 percent of severely ill patients (as per triage tool) are getting detected and admitted within one day of diagnosis. The admission of severely ill patients (triage-positive) has improved over the years: 67 percent in 2022, 86 percent in 2023 and 91 percent in 2024. The median admission duration was five days in 2022 and this has improved to seven days in 2023 and 2024. Over the years, the focus has been to ensure quality comprehensive assessment and inpatient care during the admission of the severely ill patients with focus on therapeutic nutrition for very severely undernourished patients as half of those eligible for admission have very severe undernutrition. Between April 2022 and June 2023, as per details shared by ICMR-NIE scientists, 66,765 of 72,404 notified adults were triaged, and 7,950 were triage-positive (identified as severely sick due to TB). Among these, 5,870 (or 74 percent) patents were referred and admitted. The analysis later showed 21 percent decline in early TB death rate and 11 percent reduction in overall TB death rate during treatment. By improving the admission among triage-positive patients, there is scope to further reduce TB death rate, the researchers noted, adding that once the goal of 30 percent mortality rate reduction among notified TB patients using this strategy is achieved, they will consider adding follow up triaging for all patients at two months for further reduction in mortality rate. As per the Sustainable Development Goals (SDG), India has to eliminate TB by 2030. (Edited by Ajeet Tiwari) Also Read: COVID-19 vaccines linked to cardiac-related deaths? Siddaramaiah, Biocon founder Shaw spar on X
