Preclinical murine models for the testing of antimicrobials against Mycobacterium abscessus pulmonary infections: Current practices and recommendations.

Mycobacterium abscessus, a rapidly growing nontuberculous mycobacterium, is increasingly recognized as an important pathogen of the human lung, disproportionally affecting people with cystic fibrosis (CF) and other susceptible individuals with non-CF bronchiectasis and compromised immune functions. M. abscessus infections are extremely difficult to treat due to intrinsic resistance to many antibiotics, including most anti-tuberculous drugs. Current standard-of-care chemotherapy is long, includes multiple oral and parenteral repurposed drugs, and is associated with significant toxicity. The development of more effective oral antibiotics to treat M. abscessus infections has thus emerged as a high priority. While murine models have proven instrumental in predicting the efficacy of therapeutic treatments for M. tuberculosis infections, the preclinical evaluation of drugs against M. abscessus infections has proven more challenging due to the difficulty of establishing a progressive, sustained, pulmonary infection with this pathogen in mice. To address this issue, a series of three workshops were hosted in 2023 by the Cystic Fibrosis Foundation (CFF) and the National Institute of Allergy and Infectious Diseases (NIAID) to review the current murine models of M. abscessus infections, discuss current challenges and identify priorities toward establishing validated and globally harmonized preclinical models. This paper summarizes the key points from these workshops. The hope is that the recommendations that emerged from this exercise will facilitate the implementation of informative murine models of therapeutic efficacy testing across laboratories, improve reproducibility from lab-to-lab and accelerate preclinical-to-clinical translation.

New drugs to treat difficult tuberculous and nontuberculous mycobacterial pulmonary disease.

PURPOSE OF REVIEW: Treatment of drug-sensitive tuberculosis (TB) is effective, whereas that of multidrug-resistant and extensively drug-resistant TB as well as nontuberculous mycobacterial (NTM) disease are less so. Therapy in general requires good adherence to potentially toxic drug regimens over prolonged periods. Poor adherence is associated with resistance development and poor outcome. This review will present promising new treatments, both new drugs and regimens, for difficult mycobacterial pulmonary infections. RECENT FINDINGS: A number of new and repurposed drugs including bedaquiline, delamanid, pretomanid, linezolid and clofazimine, and drug regimens, such as the The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) trial regimens, are currently progressing from basic research through clinical trials.

Discovery and validation of new antitubercular compounds as potential drug leads and probes.

Increasing multidrug resistance in Mycobacterium tuberculosis continues to diminish the number of effective drugs available for treatment of active tuberculosis. Although there are four new products (representing three new chemical classes) in clinical development, an active, robust pipeline of new chemical entities is critical to discovery of medicines to dramatically improve or shorten length of therapy via new mechanisms of action. In the absence of major pharmaceutical industry activity in tuberculosis drug development, the National Institute of Allergy and Infectious Diseases (NIAID) has supported the development of a high throughput screen for growth inhibitors of M. tuberculosis using a chemically diverse commercial library, a compound library available through the NIH Roadmap, Molecular Libraries Screening Center Network, and other compound sources. The rationale for these screens and suggested approaches for follow-up studies to identify compounds for advanced preclinical studies and as chemical probes of critical functions in M. tuberculosis, are discussed.

High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv.

There is an urgent need for the discovery and development of new antitubercular agents that target new biochemical pathways and treat drug resistant forms of the disease. One approach to addressing this need is through high-throughput screening of medicinally relevant libraries against the whole bacterium in order to discover a variety of new, active scaffolds that will stimulate new biological research and drug discovery. Through the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (www.taacf.org), a large, medicinally relevant chemical library was screened against M. tuberculosis strain H37Rv. The screening methods and a medicinal chemistry analysis of the results are reported herein.

The evolution of extensively drug resistant tuberculosis (XDR-TB): history, status and issues for global control.

Tuberculosis (TB) is a devastating disease caused by Mycobacterium tuberculosis that killed an estimated 4000-5000 person each day during 2005. Although infections with drug sensitive strains can be effectively cured with a 6 to 9 month regimen of multiple antibiotics, the inability to deliver and complete appropriate courses of therapy on a global level has led to the selection of resistant strains over the past 50 years. The selection and spread of multiple drug resistant M. tuberculosis continued for decades leading to two operationally distinct forms of the disease, multiple drug resistant (MDR-TB) and extensively drug resistant (XDR-TB). The estimate for MDR-TB and XDR-TB cases for 2005 were 424,000 and 27,000 respectively, and the situation is worst in areas with high incidences of HIV infection. The outcome was predictable based on basic microbiological principles, and the resultant and future epidemic effectively modeled mathematically. This situation was brought to the forefront when an outbreak of XDR-TB occurred in Tugela Ferry, KwaZulu-Natal, South Africa, in 2005 and began to spread. Unfortunately, we do not know the true extent of XDR-TB globally. However, all signs point to an emerging epidemic of TB infections that will be difficult, if not impossible to cure. A few new drugs are in clinical trials, but it is too early to know the final outcome; some may fail, and none will be available for several years. The situation will continue to worsen unless more resources are made available to discover and deliver better treatment options.

New tuberculosis drugs in development.

Over the past 50 years, no new drug classes have been introduced to treat tuberculosis. Tuberculosis (TB) kills nearly two million people a year mainly in the poorest communities in the developing world. It afflicts millions more. About one third of the world's population is silently infected with TB that may erupt into disease with increased age or suppression of the immune system. Nearly nine million new active cases develop every year. The World Health Organization (WHO) declared the disease a global emergency as long ago as 1993. Although huge efforts in public health control have reduced the disease burden within most established market economies, in Africa and Asia the epidemic continues to accelerate, particularly fueled by the HIV epidemic. Furthermore, resistance to the standard drugs isoniazid and rifampicin is increasing worldwide. Since the 1990s, mycobacteria have emerged with resistance patterns rendering all currently available antibiotics ineffectual. The pharmaceutical industry has mostly abandoned TB drug development due to perceived non-profitable consumer market and the diminishing number of companies engaged in anti-infective research. The public sector and infectious disease researchers have responded to advance fundamental science and to create new chemical entities as early drug candidates. With support from research funding agencies, philanthropic donors, and the STOP-TB Partnership, new chemical tools and new approaches to effectively implement TB control programs are evolving. Advanced preclinical development and strategies for Phase III clinical trials remain gap areas that will require additional engagement from all sectors.