Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance

Romano, Keith P.; Hung, Deborah T.

doi:10.1016/j.bbamcr.2022.119407

Cited by 25 publications

(5 citation statements)

References 153 publications

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“…425 [ 24 ]. According to previous literature [ 15 , 39 ] and our pilot data (data not shown), the estimated LD 50 was 4000 mg/kg. The dosages were calculated by AOT425StatPgm based on an assumed sigma of 0.125.…”

Section: Methodssupporting

confidence: 63%

“…The downregulation of proteins associated with glycerophospholipid metabolism and lipopolysaccharide biosynthesis supports a role of GCTA in disrupting lipid metabolism. Importantly, targeting lipopolysaccharide biosynthesis has proven effective against most gram-negative bacteria, making it an appealing therapeutic approach [ 39 ]. Additionally, the membrane damage observed by TEM highlights the potential of GCTA to disrupt cell integrity and may contribute to its antibacterial properties.…”

Section: Discussionmentioning

confidence: 99%

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Battling Salmonella enteritidis infections: integrating proteomics and in vivo assessment of Galla Chinensis tannic acid

Yan,

Zheng,

et al. 2024

BMC Vet Res

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Salmonella infections pose a significant threat to animal and human health. Phytochemicals present a potential alternative treatment. Galla chinensis tannic acid (GCTA), a hydrolyzable polyphenolic compound, inhibits bacterial growth and demonstrates potential as an alternative or supplement to antibiotics to prevent Salmonella infections. However, little is known about the antimicrobial mechanism of GCTA against Salmonella. Here, we revealed 456 differentially expressed proteins upon GCTA treatment, impacting pathways related to DNA replication, repair, genomic stability, cell wall biogenesis, and lipid metabolism using TMT-labeled proteomic analysis. TEM analysis suggested altered bacterial morphology and structure post-treatment. A Salmonella-infected-mouse model indicated that GCTA administration improved inflammatory markers, alleviated intestinal histopathological alterations, and reduced Salmonella enterica serovar Enteritidis (S. Enteritidis) colonization in the liver and spleen of Salmonella-infected mice. The LD50 of GCTA was 4100 mg/kg with an oral single dose, vastly exceeding the therapeutic dose. Thus, GCTA exhibited antibacterial and anti-infective activity against S. Enteritidis. Our results provided insight into the molecular mechanisms of these antibacterial effects, and highlights the potential of GCTA as an alternative to antibiotics.

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Section: Methodssupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Battling Salmonella enteritidis infections: integrating proteomics and in vivo assessment of Galla Chinensis tannic acid

Yan,

Zheng,

et al. 2024

BMC Vet Res

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“…From Fig. 19, it is clear that both OmpC and OmpF are a part and parcel of the general regulation of LPS biosynthesis which is another potent mechanism of evading the e cacy of antibiotics (Romano et al, 2023). Hence, the role of these porins as nutrient transport agents can be exploited to improve the delivery of CBD, further increasing their intracellular concentrations.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol Interactions with Outer Membrane Proteins in Salmonella Typhimurium LT2

Ibrahim,

Ndezure,

et al. 2024

Preprint

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Cannabidiol (CBD), the non-psychoactive component of the hemp plant has tremendous potential as a novel antimicrobial agent. This study aimed at understanding the interactions between CBD and the outer membrane proteins (OMPs) of Salmonella Typhimurium LT2. Employing in silico techniques, we analyzed the binding affinities, interaction dynamics, and drug-likeness of CBD with key OMPs such as OmpA, OmpC, OmpD, OmpF, OmpX, and NompC. The molecular docking results showed that CBD exhibits varying binding affinities across the OMPs, with OmpX and NompC showing the highest binding affinity of -6.6 kcal/mol and − 6.4 kcal/mol respectively, indicating strong and stable interactions. The results also revealed several key interactions such as hydrogen bonds, Pi-stacking, and hydrophobic interactions, playing crucial roles in the stability and specificity of these protein-ligand complexes. Notable interactions were identified in OmpA with a binding affinity of -5.9 kcal/mol involving hydrogen bonds at 3.2 Å and Pi-Sigma interactions at 3.4 Å. We included phylogenetic analysis of fifty different strains of Salmonella Typhimurium, and we observed high conservation levels among the OMPs, with a sequence similarity threshold of 90%. This high conservation underscores the potential of CBD to act as a broad-spectrum antimicrobial agent. Furthermore, our comparative structural analysis revealed both conserved and variable regions within the OMPs, highlighting the significance of targeting these regions to mitigate resistance development. Using KEGG Pathway analysis, we analyzed OmpC and OmpF, given their roles in nutrient transport and permeability. The disruption of these pathways by CBD binding could impair the bacteria’s ability to manage environmental stresses and evade host immune responses. Beta-lactam resistance pathway analysis was also considered, we observed that CBD could potentially disrupt resistance mechanisms by binding to OMPs, enhancing the efficacy of existing antimicrobial treatments. In conclusion, our findings suggest that CBD, through its interaction with critical OMPs, has the potential to serve as a potent antimicrobial agent against Salmonella Typhimurium LT2. These findings lay the foundation for further studies of CBD as a novel therapeutic agent in combating bacterial infections and addressing the global challenge of antibiotic resistance.

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“…As a lipopolysaccharide (LPS) component, lipid A plays a critical role in the structural integrity of the outer membrane. While novobiocin and its analogs have been shown to affect the Lpt pathway and potentiate the activity of polymyxin 53 , no direct interaction has been reported. Overall, we found that non-inducing conditions (0% rhamnose) were sufficient to capture an antibiotic susceptibility profile and to identify the specific cellular target.…”

Section: Cimple Followed By Crispri-seq Captures Drug-target Interact...mentioning

confidence: 99%

Rationally Designed Pooled CRISPRi-Seq Uncovers an Inhibitor of Bacterial Peptidyl-tRNA Hydrolase

Rahman,

Syroegin,

Novomisky Nechcoff

et al. 2024

Preprint

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Pooled knockdown libraries of essential genes are useful tools for elucidating the mechanisms of action of antibacterial compounds, a pivotal step in antibiotic discovery. However, achieving genomic coverage of antibacterial targets poses a challenge due to the uneven proliferation of knockdown mutants during pooled growth, leading to the unintended loss of important targets. To overcome this issue, we introduce CIMPLE (CRISPRi-mediated pooled library of essential genes), a rationally designed pooled knockdown library built in a model antibiotic-resistant bacteria, Burkholderia cenocepacia. By analysing growth parameters of clonal knockdown populations of an arrayed CRISPRi library, we predicted strain depletion levels during pooled growth and adjusted mutant relative abundance, achieving genomic coverage of antibacterial targets during antibiotic exposure. We demonstrate the utility of CIMPLE for chemogenetic profiling of known antibacterials and a previously discovered bacterial growth inhibitor of a new class. CRISPRi-Seq with CIMPLE, followed by biochemical validation, revealed that the novel compound targets the ribosome-associated quality control apparatus (RQC) by inhibiting the peptidyl-tRNA hydrolase (Pth). Overall, CIMPLE leverages the advantages of arrayed and pooled CRISPRi libraries to uncover unexplored targets for antibiotic action.

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Targeting LPS biosynthesis and transport in gram-negative bacteria in the era of multi-drug resistance

Cited by 25 publications

References 153 publications

Battling Salmonella enteritidis infections: integrating proteomics and in vivo assessment of Galla Chinensis tannic acid

Battling Salmonella enteritidis infections: integrating proteomics and in vivo assessment of Galla Chinensis tannic acid

Cannabidiol Interactions with Outer Membrane Proteins in Salmonella Typhimurium LT2

Rationally Designed Pooled CRISPRi-Seq Uncovers an Inhibitor of Bacterial Peptidyl-tRNA Hydrolase

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