Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity

Sun, Alexander W.; Bulterys, Philip L.; Bartberger, Michael D.; Jorth, Peter; O'Boyle, Brendan M.; Virgil, Scott C.; Miller, Jeff F.; Stoltz, Brian M.

doi:10.1016/j.bmcl.2019.07.024

Cited by 11 publications

(8 citation statements)

References 24 publications

(24 reference statements)

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“…Accordingly, we tested the toxicity of AHA-1394 using the highly sensitive liver-derived HepG2 cell line. We determined the IC 50 of AHA-1394 at 24 h to be 50.95 μg/ml, which is comparable to many current antibiotics approved for use in the clinic; azithromycin ( Abdel-Hamid et al, 2017 ) and linezolid ( Sun et al, 2019 ) commonly used to treat S. aureus SSTIs have HepG2 IC 50 s of 42.8 μg/ml, 10.1 μg/ml, respectively.…”

Section: Discussionmentioning

confidence: 95%

Antibacterial activity of novel linear polyamines against Staphylococcus aureus

et al. 2022

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New therapeutic options are urgently required for the treatment of Staphylococcus aureus infections. Accordingly, we sought to exploit the vulnerability of S. aureus to naturally occurring polyamines. We have developed and tested the anti-staphylococcal activity of three novel linear polyamines based on spermine and norspermine. Using a panel of genetically distinct and clinically relevant multidrug resistant S. aureus isolates, including the polyamine resistant USA300 strain LAC, compound AHA-1394 showed a greater than 128-fold increase in inhibition against specific S. aureus strains compared to the most active natural polyamine. Furthermore, we show that AHA-1394 has superior biofilm prevention and biofilm dispersal properties compared to natural polyamines while maintaining minimal toxicity toward human HepG2 cells. We examined the potential of S. aureus to gain resistance to AHA-1394 following in vitro serial passage. Whole genome sequencing of two stable resistant mutants identified a gain of function mutation (S337L) in the phosphatidylglycerol lysyltransferase mprF gene. Inactivation of mutant mprF confirmed the importance of this allele to AHA-1394 resistance. Importantly, AHA-1394 resistant mutants showed a marked decrease in relative fitness and increased generation time. Intriguingly, mprF::S337L contributed to altered surface charge only in the USA300 background whereas increased cell wall thickness was observed in both USA300 and SH1000. Lastly, we show that AHA-1394 displays a particular proclivity for antibiotic potentiation, restoring sensitivity of MRSA and VRSA isolates to daptomycin, oxacillin and vancomycin. Together this study shows that polyamine derivatives are impressive drug candidates that warrant further investigation.

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Section: Discussionmentioning

confidence: 95%

Antibacterial activity of novel linear polyamines against Staphylococcus aureus

et al. 2022

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“…To reduce the side-effects of 220 (linezolid), morpholine heterocyclecontaining oxazolidinone antibiotic geminal-substituted derivatives were synthesized and evaluated. 141 220 inhibited the mitochondrial protein synthesis (MPS) activity of human ribosomes due to their high homology to bacterial ribosomes. Diverse modifications were tested, and a spirotetrahydropyran analogue 221 displayed the greatest minimum inhibitory concentration (MIC) values in a broth microdilution assay against S. aureus.…”

Section: ■ Physicochemical and In Vitromentioning

confidence: 99%

“…The improved selectivity profile of spirocyclic inhibitors is well-demonstrated in the following example. To reduce the side-effects of 220 (linezolid), morpholine heterocycle-containing oxazolidinone antibiotic geminal-substituted derivatives were synthesized and evaluated …”

Section: Physicochemical and In Vitro Pharmacological Properties Of S...mentioning

confidence: 99%

Spirocyclic Scaffolds in Medicinal Chemistry

et al. 2020

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Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to obtain spirocyclic systems. The impact of spirocycles on potency and selectivity, including the aspect of stereochemistry, is discussed. Furthermore, we examine the changes in physicochemical properties as well as in in vitro and in vivo ADME using selected studies that compare spirocyclic compounds to their nonspirocyclic counterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chemistry is discussed.

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“…Indeed, mammalian mitochondrial ribosomes have some similarities with bacterial ribosomes, in particular at the level of the linezolid-binding site (Leach et al, 2007;Santini et al, 2017). (Sun et al, 2019). The subsequent inhibition of mtDNA translation thus reduces the activity of MRC complexes that contain mtDNA-encoded proteins (De Vriese et al, 2006;Garrabou et al, 2007;Le Guillou et al, 2018;Santini et al, 2017).…”

Section: Linezolidmentioning

confidence: 99%

Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

Fromenty

2020

Food and Chemical Toxicology

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Mitochondrial DNA (mtDNA) encodes for 13 proteins involved in the oxidative phosphorylation (OXPHOS) process. In liver, genetic or acquired impairment of mtDNA homeostasis can reduce ATP output but also decrease fatty acid oxidation, thus leading to different hepatic lesions including massive necrosis and microvesicular steatosis. Hence, a severe impairment of mtDNA homeostasis can lead to liver failure and death. An increasing number of investigations report that some drugs can induce mitochondrial dysfunction and drug-induced liver injury (DILI) by altering mtDNA homeostasis. Some drugs such as ciprofloxacin, antiretroviral nucleoside reverse-transcriptase inhibitors and tacrine can inhibit hepatic mtDNA replication, thus inducing mtDNA depletion. Drug-induced reduced mtDNA levels can also be the consequence of reactive oxygen speciesmediated oxidative damage to mtDNA, which triggers its degradation by mitochondrial nucleases. Such mechanism is suspected for acetaminophen and troglitazone. Other pharmaceuticals such as linezolid and tetracyclines can impair mtDNA translation, thus selectively reducing the synthesis of the 13 mtDNA-encoded proteins. Lastly, some drugs might alter the mtDNA methylation status but the pathophysiological consequences of such alteration are still unclear. Drug-induced impairment of mtDNA homeostasis is probably under-recognized since preclinical and post-marketing safety studies do not classically investigate mtDNA levels, mitochondrial protein synthesis and mtDNA oxidative damage. 2 A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 2. Main features of the mitochondria 2.1. Structure and main components Mitochondria, whose size is ~1 µm, are intracellular organelles with two membranes (namely the outer and the inner membrane) that surround the matrix. This compartment contains numerous enzymes involved in different key oxidative pathways such as mitochondrial fatty acid oxidation (mtFAO) and pyruvate oxidation via the tricarboxylic acid (TCA) cycle. The matrix also contains the mitochondrial DNA (mtDNA) and all the components (e.g. enzymes and transcription factors) mandatory for its replication, transcription, translation and repair. However, this small genome allows only the synthesis of 13 polypeptides of the mitochondrial respiratory chain (MRC), whereas all other mitochondrial proteins (~1700) are encoded by the nuclear DNA and targeted to mitochondria (Area-Gomez and Schon, 2014; Borst and Grivell, 1981). Notably, mitochondria share different major features with bacteria including size, double-membrane structure, mode of mtDNA transcription and some components of the mtDNA translation machinery (Santini et al., 2017; Schon and Fromenty, 2015). These features are due to the fact that the precursors of mitochondria were bacteria that became endosymbiotic residents of "proto-eukaryotic" cells early in our evolutionary history (Pessayre et al., 2010). 2.2. Production of energy One major role of mitochondria is the production of energy so that these organelles...

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Incorporation of a chiral gem-disubstituted nitrogen heterocycle yields an oxazolidinone antibiotic with reduced mitochondrial toxicity

Cited by 11 publications

References 24 publications

Antibacterial activity of novel linear polyamines against Staphylococcus aureus

Antibacterial activity of novel linear polyamines against Staphylococcus aureus

Spirocyclic Scaffolds in Medicinal Chemistry

Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

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