Improving the Tuberculosis Drug Development Pipeline

Evangelopoulos, Dimitrios; McHugh, Timothy D.

doi:10.1111/cbdd.12549

Cited by 21 publications

(17 citation statements)

References 81 publications

(82 reference statements)

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“…tuberculosis (MtB) is the largest bacterial threat to humans worldwide killing over 1.5 million humans around the globe each year 34, 35 . MtB is a slow-growing or non-replicating pathogen that requires prolonged antibiotic treatments (i.e., ≥6 months), often with multiple drug combinations due to problems with drug-resistance 36–38 .…”

Section: Resultsmentioning

confidence: 99%

A Highly Potent Class of Halogenated Phenazine Antibacterial and Biofilm-Eradicating Agents Accessed Through a Modular Wohl-Aue Synthesis

Yang

Abouelhassan

Burch

et al. 2017

Sci Rep

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Unlike individual, free-floating planktonic bacteria, biofilms are surface-attached communities of slow- or non-replicating bacteria encased within a protective extracellular polymeric matrix enabling persistent bacterial populations to tolerate high concentrations of antimicrobials. Our current antibacterial arsenal is composed of growth-inhibiting agents that target rapidly-dividing planktonic bacteria but not metabolically dormant biofilm cells. We report the first modular synthesis of a library of 20 halogenated phenazines (HP), utilizing the Wohl-Aue reaction, that targets both planktonic and biofilm cells. New HPs, including 6-substituted analogues, demonstrate potent antibacterial activities against MRSA, MRSE and VRE (MIC = 0.003–0.78 µM). HPs bind metal(II) cations and demonstrate interesting activity profiles when co-treated in a panel of metal(II) cations in MIC assays. HP 1 inhibited RNA and protein biosynthesis while not inhibiting DNA biosynthesis using 3H-radiolabeled precursors in macromolecular synthesis inhibition assays against MRSA. New HPs reported here demonstrate potent eradication activities (MBEC = 0.59–9.38 µM) against MRSA, MRSE and VRE biofilms while showing minimal red blood cell lysis or cytotoxicity against HeLa cells. PEG-carbonate HPs 24 and 25 were found to have potent antibacterial activities with significantly improved water solubility. HP small molecules could have a dramatic impact on persistent, biofilm-associated bacterial infection treatments.

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Section: Resultsmentioning

confidence: 99%

A Highly Potent Class of Halogenated Phenazine Antibacterial and Biofilm-Eradicating Agents Accessed Through a Modular Wohl-Aue Synthesis

Yang

Abouelhassan

Burch

et al. 2017

Sci Rep

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“…Mycobacterium tuberculosis (MtB) is as low-growing bacterial pathogen [122,123] and the leadingk iller of adults worldwide, causing > 1.5 milliond eathsi n2 017. [124,125] MtB'sp ersistent nature,a long with antibiotic resistance, has led to significant challenges regarding effective treatment options for individuals with TB infections.W eh ave evaluated select HP analogues for antibacteriala ctivity against MtB.…”

Section: Identification Of Halogenated Phenazines With Antituberculosmentioning

confidence: 99%

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

2019

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Bacterial biofilms are surface‐attached communities of slow‐growing and non‐replicating persister cells that demonstrate high levels of antibiotic tolerance. Biofilms occur in nearly 80 % of infections and present unique challenges to our current arsenal of antibiotic therapies, all of which were initially discovered for their abilities to target rapidly dividing, free‐floating planktonic bacteria. Bacterial biofilms are credited as the underlying cause of chronic and recurring bacterial infections. Innovative approaches are required to identify new small molecules that operate through bacterial growth‐independent mechanisms to effectively eradicate biofilms. One source of inspiration comes from within the lungs of young cystic fibrosis (CF) patients, who often endure persistent Staphylococcus aureus infections. As these CF patients age, Pseudomonas aeruginosa co‐infects the lungs and utilizes phenazine antibiotics to eradicate the established S. aureus infection. Our group has taken a special interest in this microbial competition strategy and we are investigating the potential of phenazine antibiotic‐inspired compounds and synthetic analogues thereof to eradicate persistent bacterial biofilms. To discover new biofilm‐eradicating agents, we have established an interdisciplinary research program involving synthetic medicinal chemistry, microbiology and molecular biology. From these efforts, we have identified a series of halogenated phenazines (HPs) that potently eradicate bacterial biofilms, and future work aims to translate these preliminary findings into ground‐breaking clinical advances for the treatment of persistent biofilm infections.

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“…The majority (40.1%) of identified phosphoproteins in this case were involved in regulation of metabolism. Again, these findings indicate that phosphorylation plays an important role in the slower metabolism of BCG, which may ultimately increase the capability for persistence within the host, and may be beneficial to the bacteria when faced with drug treatment (Evangelopoulos and McHugh, 2015 ).…”

Section: Comparative Phosphoproteomic Analysis Of Mycobacteriamentioning

confidence: 99%

Mass Spectrometry Offers Insight into the Role of Ser/Thr/Tyr Phosphorylation in the Mycobacteria

et al. 2016

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Phosphorylation is a post translational modification which can rapidly regulate biochemical pathways by altering protein function, and has been associated with pathogenicity in bacteria. Once engulfed by host macrophages, pathogenic bacteria are exposed to harsh conditions and must respond rapidly in order to survive. The causative agent of TB, Mycobacterium tuberculosis, is unusual amongst the bacteria because it can survive within the host macrophage for decades in a latent state, demonstrating a remarkable capacity to successfully evade the host immune response. This ability may be mediated in part by regulatory mechanisms such as ser/thr/tyr phosphorylation. Mass spectrometry-based proteomics has afforded us the capacity to identify hundreds of phosphorylation sites in the bacterial proteome, allowing for comparative phosphoproteomic studies in the mycobacteria. There remains an urgent need to validate the reported phosphosites, and to elucidate their biological function in the context of pathogenicity. However, given the sheer number of putative phosphorylation events in the mycobacterial proteome, and the technical difficulty of assigning biological function to a phosphorylation event, it will not be trivial to do so. There are currently six published phosphoproteomic investigations of a member of mycobacteria. Here, we combine the datasets from these studies in order to identify commonly detected phosphopeptides and phosphosites in order to present high confidence candidates for further validation. By applying modern mass spectrometry-based techniques to improve our understanding of phosphorylation and other PTMs in pathogenic bacteria, we may identify candidates for therapeutic intervention.

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Improving the Tuberculosis Drug Development Pipeline

Cited by 21 publications

References 81 publications

A Highly Potent Class of Halogenated Phenazine Antibacterial and Biofilm-Eradicating Agents Accessed Through a Modular Wohl-Aue Synthesis

A Highly Potent Class of Halogenated Phenazine Antibacterial and Biofilm-Eradicating Agents Accessed Through a Modular Wohl-Aue Synthesis

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

Mass Spectrometry Offers Insight into the Role of Ser/Thr/Tyr Phosphorylation in the Mycobacteria

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