Research Project
10201364
ABSTRACT: The major goal of this proposal is to investigate the potential for teixobactin, our newly discovered antibiotic, to treat respiratory infections. As reported in 2019 by the CDC, pneumonia caused by drug resistant Streptococcus pneumoniae, as well as methicillin-resistant Staphylococcus aureus (MRSA), are considered serious threats. In addition, respiratory bacterial co-infections with Covid-19 have recently been recognized as a significant problem. Haemophilus influenzae and Moraxella catarrhalis are two other respiratory pathogens particularly problematic in patients with chronic obstructive pulmonary disease and are common causes of community-acquired bacterial pneumonia (CABP). The most remarkable, and unexpected property of teixobactin is the lack of any detectable resistance to this compound. Teixobactin hits two related targets?lipid II, precursor of peptidoglycan and lipid III, precursor of wall teichoic acid. These highly conserved targets are not mutable?they are not proteins and are not directly coded by DNA. Since our discovery of teixobactin, we and others have failed to generate resistant mutants in any species including S. aureus, Mycobacterium tuberculosis or Bacillus anthracis. Teixobactin is highly efficacious in animal models of thigh, lung and blood infections. Animal infection models predict that the human dose of teixobactin for acute skin and skin structure infections (ABSSSI) will be very low (?1 mg/kg/day), which is advantageous, as a low dose may minimize side effects and reduce manufacturing costs. Teixobactin is in preclinical development as an intravenous (IV) drug for treating skin infections caused by pathogens such as MRSA. A pre-Investigational New Drug (IND) meeting with FDA was held in December 2018 whereby the FDA generally agreed with our development plan. An IND submission for ABSSSI is planned for 2022. In this project, Aim 1 will produce enough teixobactin for all the proposed studies. Aim 2 will conduct efficacy and PK/PD studies in animal models of pneumonia. Aim 3 will test in vitro susceptibility, bactericidal activity, post antibiotic effect (PAE) and resistance in recent clinical isolates from respiratory infections. Aim 4 will prepare and submit an IND application for intravenous treatment of a respiratory infection. Aim 5 will explore alternative routes of TXB administration (inhalation and intramuscular delivery), which would be particularly useful for outpatient treatment of respiratory and other infections. With successful completion of these projects, we will have demonstrated the promise of teixobactin for treating drug resistant respiratory infections and explored more convenient routes of TXB administration.
