Proton Motive Force Inhibitors Are Detrimental to Methicillin-Resistant Staphylococcus aureus Strains

Mohiuddin, Sayed Golam; Ghosh, Sreyashi; Kavousi, Pouria; Orman, Mehmet A.

doi:10.1128/spectrum.02024-22

Cited by 12 publications

(9 citation statements)

References 80 publications

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“…In agreement with our results, previous studies have shown that PMF is essential for starvation-induced tolerance in both gram-negative and gram-positive bacteria, including S. aureus 33,34,44 . Hence, these findings support the idea of applying PMF inhibitors to combat antibiotic-tolerant bacteria, including S. aureus 45,46 .…”

Section: Discussionsupporting

confidence: 79%

(p)ppGpp-mediated GTP homeostasis ensures the survival and antibiotic tolerance ofStaphylococcus aureusduring starvation by preserving the proton motive force

Salzer,

Ingrassia,

Sauer

et al. 2024

Preprint

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Upon nutrient limitation bacteria enter a nongrowing state, which allow bacterial survival and antibiotic tolerance. The mechanisms whether and how the messenger molecule (p)ppGpp contributes to the transition in Firmicutes is debated. Here we show forStaphylococcus aureusthat (p)ppGpp-dependent restriction of the GTP pool is essential for the culturability of starved cells and for antibiotic tolerance. Elevated GTP levels in a starving (p)ppGpp-deficient mutant lead to a division-incompetent, dormant state characterized by reduced metabolic activity and alterations in membrane function and architecture. GTP level control of nucleotide sensitive promoters result in transcriptional downregulation of gene of the TCA cycle and electron transport chain. Increasing transcription ofqoxABCD, a terminal oxidase of the respiratory chain, through mutation of the transcriptional start site partially restored the culturability of the (p)ppGpp-deficient mutant. Furthermore, we showed that the maintenance of proton motive force under nutritional stress contributes to antibiotic tolerance, supporting the idea of applying (p)ppGpp or PMF inhibitors to combat antibiotic-tolerant bacteria.

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Section: Discussionsupporting

confidence: 79%

(p)ppGpp-mediated GTP homeostasis ensures the survival and antibiotic tolerance ofStaphylococcus aureusduring starvation by preserving the proton motive force

Salzer,

Ingrassia,

Sauer

et al. 2024

Preprint

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“…In most cases, PMF remains stable as mutual compensation and transformation exist between its two components 36 . Specifically, the dissipation of ΔΨ increases the ΔpH to equilibrate and vice versa 37 . As a testing index, a hydrophobic fluorescent probe 3,3ʹ‐dipropylthiacarbocyanine iodide (DiSC 3 (5)) is used to probe the dissipation of ΔΨ (Figure 2A).…”

Section: Functions and Characterizations Of Pmf In Bacteriamentioning

confidence: 99%

“…36 Specifically, the dissipation of ΔΨ increases the ΔpH to equilibrate and vice versa. 37 As a testing index, a hydrophobic fluorescent probe 3,3ʹ-dipropylthiacarbocyanine iodide (DiSC 3 (5)) is used to probe the dissipation of ΔΨ (Figure 2A). 38 DiSC 3 (5) is a kind of membrane-labeling fluorescence probe, which is sensitive to small changes of membrane potential (ΔΨ) or membrane configuration.…”

Section: Functions and Characterizations Of Pmf In Bacteriamentioning

confidence: 99%

Bacterial proton motive force as an unprecedented target to control antimicrobial resistance

Yang

Tong

Shi

et al. 2023

Medicinal Research Reviews

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Novel antibacterial therapies are urgently required to tackle the increasing number of multidrug‐resistant pathogens. Identification of new antimicrobial targets is critical to avoid possible cross‐resistance issues. Bacterial proton motive force (PMF), an energetic pathway located on the bacterial membrane, crucially regulates various biological possesses such as adenosine triphosphate synthesis, active transport of molecules, and rotation of bacterial flagella. Nevertheless, the potential of bacterial PMF as an antibacterial target remains largely unexplored. The PMF generally comprises electric potential (ΔΨ) and transmembrane proton gradient (ΔpH). In this review, we present an overview of bacterial PMF, including its functions and characterizations, highlighting the representative antimicrobial agents that specifically target either ΔΨ or ΔpH. At the same time, we also discuss the adjuvant potential of bacterial PMF‐targeting compounds. Lastly, we highlight the value of PMF disruptors in preventing the transmission of antibiotic resistance genes. These findings suggest that bacterial PMF represents an unprecedented target, providing a comprehensive approach to controlling antimicrobial resistance.

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“…Previous research has shown that carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a mitochondria-targeted inhibitor, can inhibit STING-mediated IFN-β production by disrupting the mitochondrial membrane potential. 31 As illustrated in Fig. 5A, HeLa cells were treated with CCCP (5.0 μM), and the mitochondria were labeled with MTG.…”

Section: B and Cmentioning

confidence: 99%

Lysosome passivation triggered by silver nanoparticles enhances subcellular-targeted drug therapy

Wang,

Zhao,

Fang

et al. 2024

Nanoscale

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Proton Motive Force Inhibitors Are Detrimental to Methicillin-Resistant Staphylococcus aureus Strains

Cited by 12 publications

References 80 publications

(p)ppGpp-mediated GTP homeostasis ensures the survival and antibiotic tolerance ofStaphylococcus aureusduring starvation by preserving the proton motive force

(p)ppGpp-mediated GTP homeostasis ensures the survival and antibiotic tolerance ofStaphylococcus aureusduring starvation by preserving the proton motive force

Bacterial proton motive force as an unprecedented target to control antimicrobial resistance

Lysosome passivation triggered by silver nanoparticles enhances subcellular-targeted drug therapy

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