Natural products acting against <i>S. aureus</i> through membrane and cell wall disruption

Kumar, Gaurav; Engle, Kritika

doi:10.1039/d2np00084a

Cited by 11 publications

(3 citation statements)

References 182 publications

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“…In bacteria, the cell membrane provides a protective barrier as well as proper permeability and maintains the osmotic pressure within bacteria, which is crucial for the integrity of cell walls. − It has been found that when the fatty acids of MRSA decreased, the cell membrane of MRSA was destabilized and destroyed, which further caused cell wall damage . Given the results of fluorescence assays, we performed Gram-staining experiments to examine the effects of compounds n31 and n39 on the cell walls of MRSA.…”

Section: Resultsmentioning

confidence: 99%

Discovery and Optimization of Novel SaFabI Inhibitors as Specific Therapeutic Agents for MRSA Infection

Zhang,

Yang,

et al. 2024

J. Med. Chem.

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As the rate-limiting enzyme in fatty acid biosynthesis, Staphylococcus aureus enoyl-acyl carrier protein reductase (SaFabI) emerges as a compelling target for combating methicillinresistant S. aureus (MRSA) infections. Herein, compound 1, featuring a 4-(1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one scaffold, was identified as a potent SaFabI inhibitor (IC 50 = 976.8 nM) from an in-house library. Subsequent optimization yielded compound n31, with improved inhibitory efficacy on enzymatic activity (IC 50 = 174.2 nM) and selective potency against S. aureus (MIC = 1−2 μg/mL). Mechanistically, n31 directly inhibited SaFabI in cellular contexts. Moreover, n31 exhibited favorable safety and pharmacokinetic profiles, and dose-dependently treated MRSA-induced skin infections, outperforming the approved drug, linezolid. The chiral separation of n31 resulted in (S)-n31, with superior activities (IC 50 = 94.0 nM, MIC = 0.25−1 μg/mL) and in vivo therapeutic efficacy. In brief, our research proposes (S)-n31 as a promising candidate for SaFabI-targeted therapy, offering specific anti-S. aureus efficacy and potential for further development.

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Section: Resultsmentioning

confidence: 99%

Discovery and Optimization of Novel SaFabI Inhibitors as Specific Therapeutic Agents for MRSA Infection

Zhang,

Yang,

et al. 2024

J. Med. Chem.

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“…To better address the challenge of resistance, it is necessary to develop new agents for controlling KBC and discover new drug targets against Psa . Finding novel compounds from structurally diverse biocontrol bacteria and identifying new targets for drug action is a meaningful and challenging task . Fortunately, researchers have shifted their focus from only studying the antagonistic effects of biocontrol bacteria against Psa to also investigating the active compounds they produce .…”

Section: Introductionmentioning

confidence: 99%

Streptothricin-F Inhibition of FtsZ Function: A Promising Approach for Controlling Pseudomonas syringae pv. actinidiae

Wang,

Mi,

Mao

et al. 2024

J. Agric. Food Chem.

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Pseudomonas syringae pv. actinidiae (Psa) is a significant pathogenic bacterium affecting the kiwifruit industry. This study investigated the target sites of streptothricin-F (ST-F), produced by Streptomyces lavendulae gCLA4. The inhibition of ST-F on Psa was examined by the microscopic structural differences of Psa before and after treatment with ST-F, as well as the interaction between ST-F and cell division-related proteins. The results revealed filamentation of Psa after ST-F treatment, and fluorescence microscopy showed that ST-F inhibited the formation of the Z-ring composed of FtsZ protein. In vitro experiments and molecular docking demonstrated that ST-F can bind to FtsZ with a binding energy of 0.4 μM and inhibit FtsZ's GTP-dependent polymerization reaction. In addition, ST-F does not exert inhibitory effects on cell division in Psa strains overexpressing f tsZ. In conclusion, FtsZ is one of the target sites for ST-F inhibition of Psa, highlighting its potential as a therapeutic target for controlling Psa-induced kiwifruit bacterial canker.

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“…It can become even more difficult when analyzing compounds that target the cell envelope, since the cell wall and membrane(s) are closely connected, both structurally and functionally. Yet, cell wall synthesis is still the most successful and common clinical antibiotic target, and the cytoplasmic membrane has moved more and more into the spotlight of antibacterial drug discovery ( 27 , 28 ).…”

Section: Introductionmentioning

confidence: 99%

Dissecting antibiotic effects on the cell envelope using bacterial cytological profiling: a phenotypic analysis starter kit

Schäfer,

Sidarta,

Abdelmesseh Nekhala

et al. 2024

Microbiol Spectr

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Phenotypic analysis assays such as bacterial cytological profiling (BCP) have become increasingly popular for antibiotic mode of action analysis. A plethora of dyes, protein fusions, and reporter strains are available and have been used for this purpose, enabling both rapid mode of action categorization and in-depth analysis of antibiotic mechanisms. However, non-expert researchers may struggle choosing suitable assays and interpreting results. This is a particular problem for antibiotics that have multiple or complex targets, such as the bacterial cell envelope. Here, we set out to curate a minimal set of accessible and affordable phenotypic assays that allow distinction between membrane and cell wall targets, can identify dual-action inhibitors, and can be implemented in most research environments. To this end, we employed BCP, membrane potential, fluidity, and cell wall synthesis assays. To assess specificity and ease of interpretation, we tested three well-characterized and commercially available reference antibiotics: the potassium ionophore valinomycin, the lipid II-binding glycopeptide vancomycin, and the dual-action lantibiotic nisin, which binds lipid II and forms a membrane pore. Based on our experiments, we suggest a minimal set of BCP, a membrane-potentiometric probe, and fluorescent protein fusions to MinD and MreB as basic assay set and recommend complementing these assays with Laurdan-based fluidity measurements and a PliaI reporter fusion, where indicated. We believe that our results can provide guidance for researchers who wish to use phenotypic analysis for mode of action studies but do not possess the specialized equipment or expert knowledge to employ the full breadth of possible techniques. IMPORTANCE Phenotypic analysis assays using specialized fluorescence fusions and dyes have become increasingly popular in antibiotic mode of action analysis. However, it can be difficult to implement these methods due to the need for specialized equipment and/or the complexity of bacterial cell biology and physiology, making the interpretation of results difficult for non-experts. This is especially problematic for compounds that have multiple or pleiotropic effects, such as inhibitors of the bacterial cell envelope. In order to make phenotypic analysis assays accessible to labs, whose primary expertise is not bacterial cell biology, or with limited equipment and resources, a set of simple and broadly accessible assays is needed that is easy to implement, execute, and interpret. Here, we have curated a set of assays and strains that does not need highly specialized equipment, can be performed in most labs, and is straightforward to interpret without knowing the intricacies of bacterial cell biology.

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Natural products acting against S. aureus through membrane and cell wall disruption

Abstract: This review article highlights the mechanistic insight of the natural products that directly inhibit the Staphylococcus aureus membrane and its membrane biosynthetic enzymes by targeting membrane-embedded proteins.

Cited by 11 publications

References 182 publications

Discovery and Optimization of Novel SaFabI Inhibitors as Specific Therapeutic Agents for MRSA Infection

Discovery and Optimization of Novel SaFabI Inhibitors as Specific Therapeutic Agents for MRSA Infection

Streptothricin-F Inhibition of FtsZ Function: A Promising Approach for Controlling Pseudomonas syringae pv. actinidiae

Dissecting antibiotic effects on the cell envelope using bacterial cytological profiling: a phenotypic analysis starter kit

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