Inhibiting fatty acid synthesis overcomes colistin resistance

Carfrae, Lindsey A; Rachwalski, Kenneth; French, Shawn; Gordzevich, Rodion; Seidel, Laura; Tsai, Caressa N.; Tu, Megan M.; MacNair, Craig R.; Ovchinnikova, Olga G.; Clarke, Bradley R.; Whitfield, Chris; Brown, Eric D.

doi:10.1038/s41564-023-01369-z

Cited by 24 publications

(14 citation statements)

References 71 publications

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“…This mechanism differs from drugs that directly disrupt bacterial membranes, exhibiting broad-spectrum bactericidal effects on the same bacterial species. Interestingly, it demonstrated the requirement for colistin resistance, which was consistent with the observations of Carfrae et al but in contrast to the broad-spectrum applicability of niclosamide to Gram-negative bacteria described by Domalaon et al We tested whether azomycin–colistin exerted a synergistic effect on other COL-R Gram-negative bacteria. The results indicated that azomycin–colistin does not exerted a synergistic antibacterial effect on E.…”

Section: Discussionsupporting

confidence: 86%

“…Following an incubation period at 37 °C for 18−24 h, the slides were delicately taken out and rinsed. Each sample underwent fixation in 2.5% (v/v) glutaraldehyde at 4 °C for 4 h. Following drying, the samples were dehydrated using an ethanol gradient (30,50,70,90, and 100% vol/vol), with each gradient step lasting 2 min. After a 2 h drying period, the samples were observed using an SEM (S-3000N, Japan).…”

Section: ■ Methodsmentioning

confidence: 99%

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Azomycin Orchestrate Colistin-Resistant Enterobacter cloacae Complex’s Colistin Resistance Reversal In Vitro and In Vivo

Hu,

Chen,

Zhao

et al. 2024

ACS Infect. Dis.

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The Enterobacter cloacae complex (ECC) is a group of nosocomial pathogens that pose a challenge in clinical treatment due to its intrinsic resistance and the ability to rapidly acquire resistance. Colistin was reconsidered as a last-resort antibiotic for combating multidrug-resistant ECC. However, the persistent emergence of colistin-resistant (COL-R) pathogens impedes its clinical efficacy, and novel treatment options are urgently needed. We propose that azomycin, in combination with colistin, restores the susceptibility of COL-R ECC to colistin in vivo and in vitro. Results from the checkerboard susceptibility, time-killing, and live/dead bacterial cell viability tests showed strong synergistic antibacterial activity in vitro. Animal infection models suggested that azomycin−colistin enhanced the survival rate of infected Galleria mellonella and reduced the bacterial load in the thighs of infected mice, highlighting its superior in vivo synergistic antibacterial activity. Crystal violet staining and scanning electron microscopy unveiled the in vitro synergistic antibiofilm effects of azomycin−colistin. The safety of azomycin and azomycin−colistin at experimental concentrations was confirmed through cytotoxicity tests and an erythrocyte hemolysis test. Azomycin−colistin stimulated the production of reactive oxygen species in COL-R ECC and inhibited the PhoPQ two-component system to combat bacterial growth. Thus, azomycin is feasible as a colistin adjuvant against COL-R ECC infection.

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Section: Discussionsupporting

confidence: 86%

Section: ■ Methodsmentioning

confidence: 99%

Azomycin Orchestrate Colistin-Resistant Enterobacter cloacae Complex’s Colistin Resistance Reversal In Vitro and In Vivo

Hu,

Chen,

Zhao

et al. 2024

ACS Infect. Dis.

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“…[7][8][9][10][11] In addition, inhibition of the FAS II pathway has been shown to overcome resistance against the last resort antibiotic colistin. 12 The drug isoniazid which targets the enoyl-ACP reductase FabI (Figure 1a) is in clinical use against tuberculosis, further validating this pathway. The FAS II pathway is also present in mitochondria of human cells, but its role is not entirely clear and short-term inhibition by antibiotics should be tolerated.…”

Section: Introductionmentioning

confidence: 92%

New starting points for antibiotics targeting P. aeruginosa FabF discovered by crystallographic fragment screening followed by hit expansion

Georgiou,

Espeland,

Bukya

et al. 2023

Preprint

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There is an urgent need for new antibiotics. FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target. Very few inhibitors of FabF are known and most are derived from natural products. In an effort to further explore the chemical space of FabF ligands, we have carried out fragment screening by X-ray crystallography against an intermediated state-mimicking variant of P. aeruginosa FabF (PaFabF C164Q). This screen has screen resulted in 16 hits binding in or close to the malonyl-CoA or fatty acid binding site or an adjacent dimer interface. More than 80 analogues of the hit compounds have been explored making use of either commercially available or synthesised compounds. For 8 of those co-crystal structures could be determined and the most potent ligand has a binding affinity of 65 µM. This data package forms a strong foundation for the development of more potent and diverse FabF inhibitors.

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“…To specifically inhibit FASN, a synthetic analog called C75 was developed due to the fact that it also inhibits the biosynthesis of sterols by inhibiting β-hydroxy-β-methylglutaryl-CoA synthetase, as cerulenin does ( 109 ). The administration of cerulenin and C75 resulted in a decline in food intake and weight in mice ( 110 , 111 ). This effect is likely attributed to the elevation of malonyl-CoA levels within the hypothalamus, consequently impeding the appetite signal of the hypothalamus that is typically induced by fasting ( 112 ).…”

Section: Medications Aimed At Regulating Lipid Metabolism In Masldmentioning

confidence: 99%

Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic

Rao,

Peng,

et al. 2023

Front. Med.

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Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly defined as non-alcoholic fatty liver disease (NAFLD), is a disorder marked by the excessive deposition of lipids in the liver, giving rise to a spectrum of liver pathologies encompassing steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma. Despite the alarming increase in its prevalence, the US Food and Drug Administration has yet to approve effective pharmacological therapeutics for clinical use. MASLD is characterized by the accretion of lipids within the hepatic system, arising from a disarray in lipid provision (whether through the absorption of circulating lipids or de novo lipogenesis) and lipid elimination (via free fatty acid oxidation or the secretion of triglyceride-rich lipoproteins). This disarray leads to the accumulation of lipotoxic substances, cellular pressure, damage, and fibrosis. Indeed, the regulation of the lipid metabolism pathway is intricate and multifaceted, involving a myriad of factors, such as membrane transport proteins, metabolic enzymes, and transcription factors. Here, we will review the existing literature on the key process of lipid metabolism in MASLD to understand the latest progress in this molecular mechanism. Notably, de novo lipogenesis and the roles of its two main transcription factors and other key metabolic enzymes are highlighted. Furthermore, we will delve into the realm of drug research, examining the recent progress made in understanding lipid metabolism in MASLD. Additionally, we will outline prospective avenues for future drug research on MASLD based on our unique perspectives.

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Inhibiting fatty acid synthesis overcomes colistin resistance

Cited by 24 publications

References 71 publications

Azomycin Orchestrate Colistin-Resistant Enterobacter cloacae Complex’s Colistin Resistance Reversal In Vitro and In Vivo

Azomycin Orchestrate Colistin-Resistant Enterobacter cloacae Complex’s Colistin Resistance Reversal In Vitro and In Vivo

New starting points for antibiotics targeting P. aeruginosa FabF discovered by crystallographic fragment screening followed by hit expansion

Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic

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