Drug development challenges in nontuberculous mycobacterial lung disease: TB to the rescue

Abstract

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is treated with multiple repurposed drugs. Chemotherapy is long and often toxic, includes parenteral drugs, and suffers from poor cure rates. There is an urgent need for more efficacious, tolerated, and oral antibiotics optimized towards the treatment of NTM-PD, adapted to the spectrum of disease. In contrast to the empty NTM pipeline, drug development for the related tuberculosis lung disease has experienced a renaissance. Here, we argue that applying lessons learned from tuberculosis will facilitate the discovery of curative oral regimens for NTM-PD.

Addressing antimicrobial resistance with the IDentif.AI platform: Rapidly optimizing clinically actionable combination therapy regimens against nontuberculous mycobacteria

“…Selecting drugs with varying MoA for combinatorial optimization enables the interrogation of interactions among different drug classes 48 . Furthermore, most regimens that are clinically available for NTM-related infections are repurposed from other indications and are not specifically optimized for major pathogens 17 . We aimed to specifically optimize and design combination therapies against M. abscessus by pairing a wide range of drug classes and repurposed drugs.…”

“…These 6 antibiotics comprised of clinically relevant NTM drugs (AMK and CLR), 2 nd line anti-MTB drugs (LZD, MEM, and LVX), and those with in vitro activity against M. abscessus (LZD and RFB). RFB, which inhibits DNA-dependent RNA polymerase in order to suppress RNA synthesis, has its target in inhibiting M. abscessus clinically validated, and it is recommended for use in M. absecessus oral treatment 17 . AMK, CLR, and LZD inhibit protein biosynthesis, and MEM interferes with the synthesis of cell wall components.…”

“…Furthermore, SOC regimens for NTM-related infections are typically prescribed with Amikacin (aminoglycoside antibiotic); however, 39% of patients experienced ototoxicity after 5.5 months (median) of Amikacin in a recent study 12 , 15 . Though these guidelines provide recommended drug combinations against NTM, further optimization in the design of combination therapies against NTM may lead to the discovery of unforeseen drug interactions and improved clinical outcomes 16 , 17 . Designing combination therapies and discovering unforeseen drug interactions in clinically actionable concentrations may facilitate the success of the regimens in clinical settings.…”

From Molecular Dynamics to Supramolecular Organization: The Role of PIM Lipids in the Originality of theMycobacterialPlasma Membrane

“…Using CG MD simulations could allow easy modifications of ratios of components -allowing understanding about drug permeability or protein behavior at different stages of infection. This could prove critical to engineering a new treatment regime for TB and non-TB Mycobacterial diseases 86 . Data availability: https://github.com/pstansfeld/PIM-lipids Atomistic systems and CG-membrane set-up can be performed using respectively CHARMM-GUI bilayer builder ( https://charmm-gui.org/input/membrane.bilayer ) and CHARMM-GUI MARTINI bilayer Maker ( https://charmm-gui.org/?doc=input/martini.bilayer ) H2020-PHC-08-2014-643381, TBVAC2020.…”

Natural products lysobactin and sorangicin A show in vitro activity against Mycobacterium abscessus complex

“…41–43 Alternatively, focusing on pharmacologically and clinically validated drug targets like peptidoglycan and RNAP might accelerate the drug discovery process. 44 Although inhibitors for these targets do not exert the most potent in vitro activity, they provide excellent building blocks for iterative medicinal chemistry optimization or alternative biotechnological approaches for compound improvement. 15 Future studies should include structure activity relationship analysis and novel formulations to improve the activity and bioavailability of the natural products LYB and SOR for the development of M. abscessus antibiotics.…”