Tuberculosis (TB) has coexisted with humanity since the beginning of human history. In 2022, tuberculosis (TB) was the second leading infectious killer worldwide, following COVID-19, with 1.3 million deaths reported, according to the World Health Organization. Primarily impacting the lungs, TB can cause various symptoms, including coughing, coughing up blood or mucus, chest pain, fever, chills, night sweats, weight loss, and fatigue. This bacterial infection spreads through the air when an infected person coughs, sneezes, or spits. If left untreated, TB can ultimately lead to death. The risk of developing an active infection increases in individuals who are immunocompromised, such as individuals with HIV, infants, and those who are malnourished.
The prevalence and long-standing nature of TB as an adversary are partly due to its slow progression before more severe symptoms appear. “This is a disease that can spread very slowly,” says Bernd Meibohm, PhD, professor and chair of the Department of Pharmaceutical Sciences at the UT Health Science Center College of Pharmacy. “You may not notice it initially, and then it spreads more into the population.”
To effectively treat and manage TB, it is essential to create shorter, simpler, and safer therapies. Dr. Meibohm and his research collaborators —scientist Mercedes Gonzalez Guerrero, PhD at the University of Colorado in Fort Collins, and researchers Sarah Maloney, PhD and Anthony Hickey, PhD at Research Triangle Institute—are working to develop treatment options that require fewer pills, shorter treatment periods (ideally 2-3 months), and consist of 3-4 medications that reduce the risk of resistance while minimizing toxicity. The research team recently received a $4 million grant from the National Institutes of Health to improve treatment options for TB with these goals in mind.
Fortunately, TB is curable. However, the treatment process is lengthy and may require a combination of drugs for up to 18 months. “The standard treatment for drug-sensitive tuberculosis lasts six months,” says Dr. Meibohm. “It becomes even more complicated with drug-resistant tuberculosis, where the bacteria develop specific defenses against standard antibiotics.”
This prolonged therapy has its challenges. For instance, a patient who initially adheres to the treatment may stop taking the medication once the worst symptoms vanish if they are not adequately informed about the risks of reemergence of their infection. In addition, if therapy is not followed as prescribed, the patient risks developing a drug-resistant strain of TB, which is much harder to treat. “If you tell someone you have to take this drug therapy now for a year or longer, a handful of pills every day, that’s where it falls apart,” says Dr. Meibohm, “Usually, people are motivated for the first six weeks if that long, and then they slack off, and then you may ultimately develop drug-resistant TB. So, shortening of therapy and more efficacious therapy to overcome resistance are urgently needed.”
The newest treatment regimen against drug-resistant TB strains consists of a six-month course of three oral drugs: bedaquiline, pretomanid, and linezolid (BPaL regimen), which has proven to be nearly 90% effective. However, there is a significant drawback: linezolid is usually intended only for short-term use of a few days and can be toxic with long-term administration, leading to adverse effects. Dr. Meibohm’s team aims to replace linezolid in the treatment combination. “Linezolid is really the problem, right? So, we tried to get rid of it, and that was our starting point,” he states.
The research team has proposed inhaled Spectinamide 1810 as a replacement for linezolid—Spectinamide 1810, a semisynthetic aminocyclitol antibiotic that shows promise as a treatment for TB. Discovered at UT Health Science Center, Spectinamide 1810 has been studied by UT Health Science Center College of Pharmacy researchers working with former faculty member Richard Lee, PhD (now at St. Jude Children’s Research Hospital) for over a decade. Spectinamide 1810 is considered relatively safe for long-term use. Another advantage of Spectinamide 1810 is that it can be directly administered to the lungs as a dry powder inhalation. The research team believes that replacing linezolid with Spectinamide 1810 in the traditional BPaL regimen will be just as effective in treating drug-resistant TB infections without the risk of harmful side effects for the patient.
Dr. Meibohm and his team’s ongoing research marks an important advancement in the battle against tuberculosis. Given the persistent global challenge posed by TB, these innovations may lead to more effective and sustainable treatment options, ultimately enhancing outcomes for millions impacted by this debilitating illness. The dedication to improving TB therapies highlights the necessity of ongoing investment in antimicrobial research and development to eliminate this long-standing adversary.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research reported in this press release was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number 1R01AI178885-01A1.