Cystic Fibrosis-Related Nontuberculous Mycobacterial Pulmonary Disease

Baird, Timothy; Bell, Scott

doi:10.1016/j.ccm.2023.06.008

Cited by 6 publications

(2 citation statements)

References 86 publications

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“…[2] Another growing healthcare concern are non-tuberculous mycobacteria (NTM), [3] such as Mycobacterium abscessus (Mabs), that can cause severe infections of various organs, foremost in the respiratory tract [4] that often require different treatment approaches in comparison to tuberculosis. [5] Patients with underlying lung conditions, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), [6] or a compromised immune system are partic-ularly susceptible to NTM infections. [7] As the bacteria are commonly found in the environment, NTM are usually acquired from soil and water sources.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides

Lang,

Ganapathy,

Mann

et al. 2024

ChemMedChem

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Nα‐aroyl‐N‐aryl‐phenylalanine amides (AAPs) are RNA polymerase inhibitors with activity against Mycobacterium tuberculosis and non‐tuberculous mycobacteria. We observed that AAPs rapidly degrade in microsomal suspensions, suggesting that avoiding hepatic metabolism is critical for their effectiveness in vivo. As both amide bonds are potential metabolic weak points of the molecule, we synthesized 16 AAP analogs in which the amide bonds are shielded by methyl or fluoro substituents in close proximity. Some derivatives show improved microsomal stability, while being plasma‐stable and non‐cytotoxic. In parallel with the metabolic stability studies, the antimycobacterial activity of the AAPs against Mycobacterium tuberculosis, Mycobacterium abscessus, Mycobacterium avium and Mycobacterium intracellulare was determined. The stability data are discussed in relation to the antimycobacterial activity of the panel of compounds and reveal that the concept of steric shielding of the anilide groups by a fluoro substituent has the potential to improve the stability and bioavailability of AAPs.

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Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides

Lang,

Ganapathy,

Mann

et al. 2024

ChemMedChem

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show abstract

“…While historically deemed harmless environmental dwellers, their potential to cause diseases in immunocompromised populations and individuals with chronic respiratory con-2 of 14 ditions like cystic fibrosis [7][8][9][10] or bronchiectasis [11] has highlighted their clinical relevance. NTM infections manifest across a spectrum of clinical presentations that includes pulmonary, cutaneous [12,13], and disseminated forms.…”

Section: Introductionmentioning

confidence: 99%

Broad-Spectrum In Vitro Activity of Nα-Aroyl-N-Aryl-Phenylalanine Amides against Non-Tuberculous Mycobacteria and Comparative Analysis of RNA Polymerases

Lang,

Ganapathy,

Abdelaziz

et al. 2024

Antibiotics

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This study investigates the in vitro activity of Nα-aroyl-N-aryl-phenylalanine amides (AAPs), previously identified as antimycobacterial RNA polymerase (RNAP) inhibitors, against a panel of 25 non-tuberculous mycobacteria (NTM). The compounds, including the hit compound MMV688845, were selected based on their structural diversity and previously described activity against mycobacteria. Bacterial strains, including the M. abscessus complex, M. avium complex, and other clinically relevant NTM, were cultured and subjected to growth inhibition assays. The results demonstrate significant activity against the most common NTM pathogens from the M. abscessus and M. avium complexes. Variations in activity were observed against other NTM species, with for instance M. ulcerans displaying high susceptibility and M. xenopi and M. simiae resistance to AAPs. Comparative analysis of RNAP β and β′ subunits across mycobacterial species revealed strain-specific polymorphisms, providing insights into differential compound susceptibility. While conservation of target structures was observed, differences in compound activity suggested influences beyond drug–target interactions. This study highlights the potential of AAPs as effective antimycobacterial agents and emphasizes the complex interplay between compound structure, bacterial genetics, and in vitro activity.

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Nα‐Aroyl‐N‐Aryl‐Phenylalanine Amides: A Promising Class of Antimycobacterial Agents Targeting the RNA Polymerase

Seidel,

Goddard,

Lang

et al. 2024

Chemistry & Biodiversity

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Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis, remains the leading cause of death from a bacterium in the world. The global prevalence of clinically relevant infections with opportunistically pathogenic non‐tuberculous mycobacteria (NTM) have also been on the rise. Pharmacological treatment of both TB and NTM infections usually requires prolonged regimens of drug combinations, and is often challenging because of developed or inherent resistance to common antibiotic drugs. Medicinal chemistry efforts are thus needed to improve treatment options and therapeutic outcomes. Nα‐aroyl‐N‐aryl‐phenylalanine amides (AAPs) have been identified as potent antimycobacterial agents that target the RNA polymerase with a low probability of cross resistance to rifamycins, the clinically most important class of antibiotics known to inhibit the bacterial RNA polymerase. In this review, we describe recent developments in the field of AAPs, including synthesis, structural characterization, in vitro microbiological profiling, structure‐activity relationships, physicochemical properties, pharmacokinetics and early cytotoxicity assessment.

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Cystic Fibrosis-Related Nontuberculous Mycobacterial Pulmonary Disease

Cited by 6 publications

References 86 publications

Synthesis and in vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides

Synthesis and in vitro Metabolic Stability of Sterically Shielded Antimycobacterial Phenylalanine Amides

Broad-Spectrum In Vitro Activity of Nα-Aroyl-N-Aryl-Phenylalanine Amides against Non-Tuberculous Mycobacteria and Comparative Analysis of RNA Polymerases

Nα‐Aroyl‐N‐Aryl‐Phenylalanine Amides: A Promising Class of Antimycobacterial Agents Targeting the RNA Polymerase

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