Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters

Kim, Wooseong; Steele, A. Duncan; Zhu, Wanpeng; Csatary, Erika E.; Fricke, Nico; Dekarske, Madeline M; Jayamani, Elamparithi; Pan, Wen; Kwon, Bumsup; Sinitsa, Isabelle; Rosen, Jake L; Conery, Annie L.; Fuchs, Beth Burgwyn; Vlahovska, Petia M.; Ausubel, Frederick M.; Gao, Huajian; Wuest, William M.; Mylonakis, Eleftherios

doi:10.1021/acsinfecdis.8b00161

Cited by 34 publications

(51 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We reported a similar result in a previous SAR study on nTZDpa (12), where we observed that nTZDpa-analogs 6 and 11 ( Fig. 4 B and C) induced rapid SYTOX Green permeabilization, but did not affect the viability of MRSA persisters (12).…”

Section: The Killing Of Mrsa Persisters Is Correlated With Increased supporting

confidence: 89%

“…Indeed, transmission electron micrographs (TEMs) showed that 10× MIC bithionol disrupts MRSA membranes, causing the intracellular formation of mesosome-like structures, abnormal cell divisions, and cell lysis (Fig. 1B), which we previously observed when S. aureus cells were treated with membrane-active antimicrobials (12).…”

Section: Resultsmentioning

confidence: 55%

“…In contrast to daptomycin, however, a subset of the membrane-active synthetic retinoids also kill nongrowing MRSA persister cells (6). In addition to the synthetic retinoids, we have described 2 additional membrane-active compounds with anti-MRSA activity: NH125, a histidine-kinase inhibitor (11), and nTZDpa, a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist (12). Although NH125 and nTZDpa have excellent anti-MRSA persister activity, they both cause substantial hemolysis of red blood cells at high concentrations (>32 μg/mL) (12,13), which is a drawback for further development as anti-MRSA therapeutic agents.…”

Section: Significancementioning

confidence: 99%

“…The membrane-active retinoids, NH125, and nTZDpa were identified by screening ∼82,000 synthetic compounds by using a high-throughput Caenorhabditis elegans-MRSA infection screening assay for compounds that block the ability of MRSA to kill the nematodes (6,11,12). We subsequently screened 185 "hit" compounds for the additional ability to permeabilize MRSA persisters by using a SYTOX Green membrane permeability assay (11).…”

Section: Significancementioning

confidence: 99%

See 3 more Smart Citations

A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus

Kim

Zou

Hari

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

132

178

View full text Add to dashboard Cite

Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membrane-active antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.

show abstract

Section: The Killing Of Mrsa Persisters Is Correlated With Increased supporting

confidence: 89%

Section: Resultsmentioning

confidence: 55%

Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus

Kim

Zou

Hari

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

132

178

View full text Add to dashboard Cite

show abstract

“…We identified several bioactive compounds, of which biological activities have been previously determined [ 20 ]. For example, the selective retinoic acid receptor γ (RARγ) agonist CD437 and CD1530 [ 19 ], the selective peroxisome proliferator-activated receptor γ (PPARγ)-agonist nTZDpa [ 21 ], the anti-parasite drug bithionol [ 22 ], and insulin-like growth factor receptor inhibitor PQ401 [ 23 ]. Each show promising antimicrobial potency against multidrug-resistant Gram-positive pathogens and their persister cells.…”

Section: Introductionmentioning

confidence: 99%

New Antimicrobial Bioactivity against Multidrug-Resistant Gram-Positive Bacteria of Kinase Inhibitor IMD0354

et al. 2020

Self Cite

View full text Add to dashboard Cite

Multidrug-resistant pathogens pose a serious threat to human health. For decades, the antibiotic vancomycin has been a potent option when treating Gram-positive multidrug-resistant infections. Nonetheless, in recent decades, we have begun to see an increase in vancomycin-resistant bacteria. Here, we show that the nuclear factor-kappa B (NF-κB) inhibitor N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (IMD0354) was identified as a positive hit through a Caenorhabditis elegans–methicillin-resistant Staphylococcus aureus (MRSA) infection screen. IMD0354 was a potent bacteriostatic drug capable of working at a minimal inhibitory concentration (MIC) as low as 0.06 µg/mL against various vancomycin-resistant strains. Interestingly, IMD0354 showed no hemolytic activity at concentrations as high as 16 µg/mL and is minimally toxic to C. elegans in vivo with 90% survival up to 64 µg/mL. In addition, we demonstrated that IMD0354′s mechanism of action at high concentrations is membrane permeabilization. Lastly, we found that IMD0354 is able to inhibit vancomycin-resistant Staphylococcus aureus (VRSA) initial cell attachment and biofilm formation at sub-MIC levels and above. Our work highlights that the NF-κB inhibitor IMD0354 has promising potential as a lead compound and an antimicrobial therapeutic candidate capable of combating multidrug-resistant bacteria.

show abstract

A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin

Heo,

Zou,

Baek

et al. 2023

Advanced Science

Self Cite

View full text Add to dashboard Cite

Infections caused by Staphylococcus aureus, notably methicillin‐resistant S. aureus (MRSA), pose treatment challenges due to its ability to tolerate antibiotics and develop antibiotic resistance. The former, a mechanism independent of genetic changes, allows bacteria to withstand antibiotics by altering metabolic processes. Here, a potent methylazanediyl bisacetamide derivative, MB6, is described, which selectively targets MRSA membranes over mammalian membranes without observable resistance development. Although MB6 is effective against growing MRSA cells, its antimicrobial activity against MRSA persisters is limited. Nevertheless, MB6 significantly potentiates the bactericidal activity of gentamicin against MRSA persisters by facilitating gentamicin uptake. In addition, MB6 in combination with daptomycin exhibits enhanced anti‐persister activity through mutual reinforcement of their membrane‐disrupting activities. Crucially, the “triple” combination of MB6, gentamicin, and daptomycin exhibits a marked enhancement in the killing of MRSA persisters compared to individual components or any double combinations. These findings underscore the potential of MB6 to function as a potent and selective membrane‐active antimicrobial adjuvant to enhance the efficacy of existing antibiotics against persister cells. The molecular mechanisms of MB6 elucidated in this study provide valuable insights for designing anti‐persister adjuvants and for developing new antimicrobial combination strategies to overcome the current limitations of antibiotic treatments.

show abstract

Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters

Cited by 34 publications

References 15 publications

A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus

A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus

New Antimicrobial Bioactivity against Multidrug-Resistant Gram-Positive Bacteria of Kinase Inhibitor IMD0354

A Methylazanediyl Bisacetamide Derivative Sensitizes Staphylococcus aureus Persisters to a Combination of Gentamicin And Daptomycin

Contact Info

Product

Resources

About