Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials

Morvan, Claire; Halpern, David; Kénanian, Gérald; Hays, Constantin; Anba‐Mondoloni, Jamila; Brinster, Sophie; Kennedy, Sean P.; Trieu-Cuot, Patrick; Poyart, Claire; Lamberet, Gilles; Gloux, Karine; Gruss, Alexandra

doi:10.1038/ncomms12944

Cited by 51 publications

(139 citation statements)

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“…The inclusion of fatty acids in primary screening media thus uncovers a new class of clinical staphylococcal fatty acid auxotrophs that are viable but nonculturable (VBNC). Fatty acid auxotrophs were previously selected in the laboratory using FabI inhibitors in the presence of fatty acids (19,29). The present results lead us to suggest that triclosan may select for successful FASII bypass variants in the human host.…”

Section: Resultsmentioning

confidence: 72%

“…In vitro-selected FASII bypass in S. aureus was associated with mutations mapping to the acc and fabD genes (6,19,29). Among 10 analyzed Exo isolates, 6 carried polymorphisms in accC, accD, or accB, including stop codons (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…About half of the Exo isolates studied here carried fabD polymorphisms, some of which mapped adjacent to a catalytic residue of the active site (Table 1) (31). Two isolates had the FabD G196R mutation (the more common amino acid at position 196 [aa 196] is glycine) that we recently showed to be responsible for FASII bypass (19). In conclusion, the acc and/or fabD polymorphism identified among FA-T r clinical and veterinary isolates is likely responsible for the observed capacity to elude FASII inhibition when fatty acids are available.…”

Section: Resultsmentioning

confidence: 99%

“…Although S. aureus was at first considered sensitive to FASII inhibitors, our recent studies demonstrated benefits from environmental fatty acids for emergence of resistant mutants (19). The question of the survival of such mutants in a clinical context remains in debate (6,7,12,19).…”

mentioning

confidence: 99%

“…The question of the survival of such mutants in a clinical context remains in debate (6,7,12,19). It is therefore essential to determine whether FASII bypass, as characterized mainly in vitro, is relevant to natural staphylococcal populations.…”

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confidence: 99%

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Clinical Relevance of Type II Fatty Acid Synthesis Bypass in Staphylococcus aureus

Gloux

Guillemet

Soler

et al. 2017

Antimicrob Agents Chemother

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The need for new antimicrobials to treat bacterial infections has led to the use of type II fatty acid synthesis (FASII) enzymes as front-line targets. However, recent studies suggest that FASII inhibitors may not work against the opportunist pathogen Staphylococcus aureus, as environmental fatty acids favor emergence of multi-anti-FASII resistance. As fatty acids are abundant in the host and one FASII inhibitor, triclosan, is widespread, we investigated whether fatty acid pools impact resistance in clinical and veterinary S. aureus isolates. Simple addition of fatty acids to the screening medium led to a 50% increase in triclosan resistance, as tested in 700 isolates. Moreover, nonculturable triclosan-resistant fatty acid auxotrophs, which escape detection under routine conditions, were uncovered in primary patient samples. FASII bypass in selected isolates correlated with polymorphisms in the acc and fabD loci. We conclude that fatty-acid-dependent strategies to escape FASII inhibition are common among S. aureus isolates and correlate with anti-FASII resistance and emergence of nonculturable variants.KEYWORDS antibiotic resistance, infection, persistence, nondetectable resistance, fatty acids, Staphylococcus aureus S taphylococcus aureus is a leading cause of a wide range of infections that can affect numerous host organs and cause a range of effects from mild symptoms to severe and life-threatening diseases. Acquisition of antimicrobial resistance, likely due to overuse of antibiotics, is the principal cause of S. aureus drug resistance (1). A class of new-generation antimicrobials in intensive development uses the type II fatty acid synthesis (FASII) pathway as an antibacterial target (2-5) to treat S. aureus infections (6-8). A widely used biocide, triclosan (5-chloro-2-[2,4-dichlorophenoxy]phenol; commercialized as Irgasan or Microban), is a prototype for further anti-FASII development (4, 9, 10).The utility of FASII inhibitors was questioned when several Gram-positive bacteria were shown to be refractory to FASII inhibitors in the presence of exogenous fatty acids, making FASII enzymes dispensable (11,12). Both free and complexed fatty acids are abundant in the host (13,14), which would facilitate FASII bypass. Reservoirs and invasion sites of clinical and community-acquired staphylococci (i.e., skin, nares, gut, blood, and organs) are naturally rich in fatty acids (13-16), and triclosan is present in the environment and in human body fluids (17,18). This combination could favor FASII bypass via emergence of triclosan-resistant variants, including fatty acid auxotrophs. Fatty-acid-dependent isolates escape detection on standard isolation media, thereby confounding diagnosis and treatment.

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Section: Resultsmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Clinical Relevance of Type II Fatty Acid Synthesis Bypass in Staphylococcus aureus

Gloux

Guillemet

Soler

et al. 2017

Antimicrob Agents Chemother

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Production of pikromycin using branched chain amino acid catabolism in Streptomyces venezuelae ATCC 15439

Kim

et al. 2018

Journal of Industrial Microbiology and Biotechnology

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Branched chain amino acids (BCAA) are catabolized into various acyl-CoA compounds, which are key precursors used in polyketide productions. Because of that, BCAA catabolism needs fine tuning of flux balances for enhancing the production of polyketide antibiotics. To enhance BCAA catabolism for pikromycin production in Streptomyces venezuelae ATCC 15439, three key enzymes of BCAA catabolism, 3-ketoacyl acyl carrier protein synthase III, acyl-CoA dehydrogenase, and branched chain α-keto acid dehydrogenase (BCDH) were manipulated. BCDH overexpression in the wild type strain resulted in 1.3 fold increase in pikromycin production compared to that of WT, resulting in total 25 mg/L of pikromycin. To further increase pikromycin production, methylmalonyl-CoA mutase linked to succinyl-CoA production was overexpressed along with BCDH. Overexpression of the two enzymes resulted in the highest titer of total macrolide production of 43 mg/L, which was about 2.2 fold increase compared to that of the WT. However, it accumulated and produced dehydroxylated forms of pikromycin and methymycin, including their derivatives as well. It indicated that activities of pikC, P450 monooxygenase, newly became a bottleneck in pikromycin synthesis.

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Effects of Triclosan on the Development of Antimicrobial Resistance in the Environment: A Review

et al. 2023

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Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials

Cited by 51 publications

References 67 publications

Clinical Relevance of Type II Fatty Acid Synthesis Bypass in Staphylococcus aureus

Clinical Relevance of Type II Fatty Acid Synthesis Bypass in Staphylococcus aureus

Production of pikromycin using branched chain amino acid catabolism in Streptomyces venezuelae ATCC 15439

Effects of Triclosan on the Development of Antimicrobial Resistance in the Environment: A Review

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