The Staphylococcus aureus FASII bypass escape route from FASII inhibitors

Morvan, Claire; Halpern, David; Kénanian, Gérald; Pathania, Amit; Anba‐Mondoloni, Jamila; Lamberet, Gilles; Gruss, Alexandra; Gloux, Karine

doi:10.1016/j.biochi.2017.07.004

Cited by 27 publications

(33 citation statements)

References 58 publications

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“…Adaptation to FASII inhibitors is not due to FASII mutations. Mutations in FASII initiation genes may 91 lead to antibiotic resistance (14,(17)(18)(19). We monitored mutations in FASII antibiotic-adapted USA300 92 or Newman strains by DNAseq, using FASII inhibitors triclosan or AFN-1252 (Table S1).…”

Section: Aureus 89 90mentioning

confidence: 99%

“…Anti-FASII 25 resistance due to mutations affecting the target enzyme or to horizontal transfer of an antibiotic-26 resistant gene homologue may occur and are often antibiotic-specific (15,16). In contrast, resistant 27 mutants that allow compensatory fatty acid utilization at both phospholipid positions were isolated 28 and also found in clinical isolates; these mutants map in FASII initiation genes distinct from the gene 29 encoding the antibiotic target protein (17)(18)(19). Despite emergence of mutations, continued FASII-30 targeted drug development is rationalized by the accepted postulate that the general wild type S. 31 aureus population must synthesize branched chain fatty acid anteiso 15:0 (ai15) to complete 32 membrane phospholipids (1, 3, 5, 8-11, 14, 20).…”

Section: Introduction 19 20mentioning

confidence: 99%

“…We investigated this postulate, and report here that 33 an alternative antibiotic adaptation mechanism is functional in host environments, which enables S. tests are decisional checkpoints for antibiotic development. FASII antibiotic challenge tests to date 40 administer treatments within minutes to a few hours post-infection (summarized in (19)), i.e., prior 41 to bacterial dissemination to host organs, and before clinical symptoms would call for antibiotic 42 treatment (21,22). This consideration guided the design of the infection and treatment protocol 43 used here (Fig.…”

Section: Introduction 19 20mentioning

confidence: 99%

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Permissive Fatty Acid Incorporation in Host Environments Promotes Staphylococcal Adaptation to FASII Antibiotics

Kénanian

Morvan

Weckel

et al. 2019

Preprint

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1Development of fatty acid synthesis pathway (FASII) inhibitors against the major human pathogen 2 Staphylococcus aureus hinges on the accepted but unproven postulate that an endogenously 3 synthesized branched chain fatty acid is required to complete membrane phospholipids. Evidence for 4 anti-FASII efficacy in animal models supported this view. However, restricted test conditions used 5 previously to show FASII antibiotic efficacy led us to investigate these questions in a broader, host-6 relevant context. We report that S. aureus rapidly adapts to FASII antibiotics without FASII mutations 7 when exposed to host environments. Treatment with a lead FASII antibiotic upon signs of infection, 8 rather than just after inoculation as commonly practiced, failed to eliminate S. aureus from infected 9 organs in a septicemia model. In vitro, addition of serum facilitated rapid S. aureus FASII bypass by 10 environmental fatty acid (eFA) replacement in phospholipids. Serum lowers membrane stress, 11 leading to increased retention of the two substrates required for exogenous fatty acid (eFA) 12 utilization. In these conditions, eFA occupy both phospholipid positions 1 and 2, regardless of anti-13 FASII selection. This study revises conclusions on S. aureus fatty acid requirements by disproving the 14 postulate of fatty acid stringency, and reveals an Achilles' heel for using FASII antibiotics to treat 15 infection in monotherapy. 16 17 18 decreased 10-fold in liver (p= ≤0.05), and unchanged in spleen. FASII antibiotic treatments thus failed 54 to eliminate S. aureus in a septicemia model. The underlying mechanisms leading to FASII inhibitor 55 escape in host-relevant conditions were investigated. 56 57 Host constituents promote rapid staphylococcal adaptation to FASII antibiotics. We reasoned that 58 in septicemic infection, serum and other host constituents bind eFA, and may neutralize FASII 59 inhibitors (2, 5, 24,25). The effect of serum on FASII antibiotic activity was tested using triclosan, an 60 extensively studied and used biocide that also targets FabI (26). S. aureus triclosan sensitivity was 61 compared in medium containing a 3-fatty-acid cocktail (called here 'FA'; with triclosan, FA-Tric), and 62 the same medium supplemented with serum (SerFA-Tric)( Fig. 2A). USA300 and Newman strain 63 growth without serum were inhibited by triclosan, with emergence of FASII mutants usually after 24-64 48 h incubation (18). However, serum supplementation markedly shortened latency compared to BHI 65

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Section: Aureus 89 90mentioning

confidence: 99%

Section: Introduction 19 20mentioning

confidence: 99%

Section: Introduction 19 20mentioning

confidence: 99%

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Permissive Fatty Acid Incorporation in Host Environments Promotes Staphylococcal Adaptation to FASII Antibiotics

Kénanian

Morvan

Weckel

et al. 2019

Preprint

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“…[16] Indeed lipid biosynthesis is a target of interest for antibacterial agents as metabolism of fatty acids is often unique to each species of bacteria. [17] Despite controversial interest of targeting such a biological pathway [18] several natural products including cerulenin and phomallenic acid C [19] are encountered in the literature. Other synthetic inhibitors are also currently in development to fight MRSA infections including CG400549 [20] and Afabicin [21] (FabI) confirming the potential of this pathway for developing narrow-spectrum antibiotics (Scheme 2).…”

mentioning

confidence: 99%

“…Other synthetic inhibitors are also currently in development to fight MRSA infections including CG400549 [20] and Afabicin [21] (FabI) confirming the potential of this pathway for developing narrow-spectrum antibiotics (Scheme 2). [18] …”

mentioning

confidence: 99%

Epoxy Isonitriles, A Unique Class of Antibiotics: Synthesis of Their Metabolites and Biological Investigations

et al. 2018

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Epoxy isonitrile containing natural products often possess specific and potent antibacterial activity against Gram-positive pathogens. This scaffold, however, is extremely labile under acidic and basic conditions, undergoing a Payne rearrangement to produce a stable epoxy ketone metabolite and releasing hydrogen cyanide. We synthesized and performed biological assays with epoxy ketone containing metabolites and identified that the epoxy isonitrile moiety is pertinent for biological activity. Serendipitously, we discovered an α,β-unsaturated epoxy ketone analogue that exhibited moderate activity against Staphylococcus aureus.

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The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl‐Acyl Carrier Protein Binding Site of FabI

et al. 2020

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The enoyl‐acyl carrier protein reductase enzyme FabI is essential for fatty acid biosynthesis in Staphylococcus aureus and represents a promising target for the development of novel, urgently needed anti‐staphylococcal agents. Here, we elucidate the mode of action of the kalimantacin antibiotics, a novel class of FabI inhibitors with clinically‐relevant activity against multidrug‐resistant S. aureus. By combining X‐ray crystallography with molecular dynamics simulations, in vitro kinetic studies and chemical derivatization experiments, we characterize the interaction between the antibiotics and their target, and we demonstrate that the kalimantacins bind in a unique conformation that differs significantly from the binding mode of other known FabI inhibitors. We also investigate mechanisms of acquired resistance in S. aureus and identify key residues in FabI that stabilize the binding of the antibiotics. Our findings provide intriguing insights into the mode of action of a novel class of FabI inhibitors that will inspire future anti‐staphylococcal drug development.

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The Staphylococcus aureus FASII bypass escape route from FASII inhibitors

Cited by 27 publications

References 58 publications

Permissive Fatty Acid Incorporation in Host Environments Promotes Staphylococcal Adaptation to FASII Antibiotics

Permissive Fatty Acid Incorporation in Host Environments Promotes Staphylococcal Adaptation to FASII Antibiotics

Epoxy Isonitriles, A Unique Class of Antibiotics: Synthesis of Their Metabolites and Biological Investigations

The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl‐Acyl Carrier Protein Binding Site of FabI

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