Novel Small-molecule Antibacterials against Gram-positive Pathogens of Staphylococcus and Enterococcus Species

Seethaler, Marius; Hertlein, Tobias; Wecklein, Björn; Ymeraj, Alba; Ohlsen, Knut; Lalk, Michael; Hilgeroth, Andreas

doi:10.3390/antibiotics8040210

Cited by 9 publications

(8 citation statements)

References 23 publications

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“…Small molecules bind non-coding RNAs and structure/function base assays can be developed to select these molecules [ 63 , 64 ]. A new class of antibacterial reagent is a novel hybrid small molecule but has yet to be shown for long-term resistance or active against biofilms [ 65 ]. We conclude that the compound PKZ18-22 is a very effective antibiotic against S. aureus biofilms.…”

Section: Discussionmentioning

confidence: 99%

A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

et al. 2021

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Combating single and multi-drug-resistant infections in the form of biofilms is an immediate challenge. The challenge is to discover innovative targets and develop novel chemistries that combat biofilms and drug-resistant organisms, and thwart emergence of future resistant strains. An ideal novel target would control multiple genes, and can be inhibited by a single compound. We previously demonstrated success against Staphylococcus aureus biofilms by targeting the tRNA-dependent regulated T-box genes, not present in the human host. Present in Gram-positive bacteria, T-box genes attenuate transcription with a riboswitch-like element that regulates the expression of aminoacyl-tRNA synthetases and amino acid metabolism genes required for cell viability. PKZ18, the parent of a family of compounds selected in silico from 305,000 molecules, inhibits the function of the conserved T-box regulatory element and thus blocks growth of antibiotic-resistant S. aureus in biofilms. The PKZ18 analog PKZ18-22 was 10-fold more potent than vancomycin in inhibiting growth of S. aureus in biofilms. In addition, PKZ18-22 has a synergistic effect with existing antibiotics, e.g., gentamicin and rifampin. PKZ18-22 inhibits the T-box regulatory mechanism, halts the transcription of vital genes, and results in cell death. These effects are independent of the growth state, planktonic or biofilm, of the bacteria, and could inhibit emergent strains.

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Section: Discussionmentioning

confidence: 99%

A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

et al. 2021

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“…The results showed that all compounds were active against the tested cells—the most significant activity was observed in compound 11026115, which killed dormant MTB H37Rv in three different in vitro models with MIC 0.250 mc/mL [ 136 ]. Recently, Seethaler et al (2019) reported their successful attempt to generate two novel thienocarbazole compounds with antimicrobial activity towards S. aureus and Enterococcus species [ 137 ]. The lowest MICs were 2 mcg/mL against S. aureus and 8 mg/mL against Enterococcus in vitro.…”

Section: Newly Prospective Pharmaceutical Candidates To Mitigate Antimicrobial Resistancementioning

confidence: 99%

Pharmaceutical Approaches on Antimicrobial Resistance: Prospects and Challenges

et al. 2021

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The rapid increase in pathogenic microorganisms with antimicrobial resistant profiles has become a significant public health problem globally. The management of this issue using conventional antimicrobial preparations frequently results in an increase in pathogen resistance and a shortage of effective antimicrobials for future use against the same pathogens. In this review, we discuss the emergence of AMR and argue for the importance of addressing this issue by discovering novel synthetic or naturally occurring antibacterial compounds and providing insights into the application of various drug delivery approaches, delivered through numerous routes, in comparison with conventional delivery systems. In addition, we discuss the effectiveness of these delivery systems in different types of infectious diseases associated with antimicrobial resistance. Finally, future considerations in the development of highly effective antimicrobial delivery systems to combat antimicrobial resistance are presented.

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“…[4][5][6] The resistance of pathogenic bacteria against antibiotics is a serious problem for the future. 7 An alternative approach is needed such as finding new modes of the action of novel antibiotics. 8 One of the solutions to finding the novel antibiotic is a computational approach.…”

Section: Introductionmentioning

confidence: 99%

Antibacterial of Dibenzo-p-Dioxi-2,8-Dicarboxylic Acid Against Pathogenic Oral Bacteria E. faecalis ATCC 29212 Peptide Pheromones: Quorum Sensing of in vitro and in silico Study

Kurnia

Rachmawati

Satari

2020

DDDT

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Background Recently, it has emerged from the international scientific literature that quorum sensing (QS) is a promising way for the effective treatment of diseases caused by pathogenic bacteria. One of the crucial proteins in the QS system of Gram-positive bacteria is the pheromone. Some research has reported secondary metabolites from natural products capable of attenuating bacteria through the interruption of the quorum sensing system. One of the Indonesian herbal plants containing bioactive compounds is Sarang Semut ( Myrmecodia pendans ). A phenolic compound, dibenzo- p -dioxin-2,8-dicarboxylic acid, has been isolated from this plant which had antibacterial activity against Enterococcus faecalis . However, the molecular mechanism of it has not been known. Aim The study in question aimed to predict the molecular action of the compound M. pendans against some proteins that act as a signal in the mediated QS of Gram-positive bacteria, called pheromones, including PrgQ, PrgX, PrgZ, and CcfA. Materials and Methods The methods used in this in silico study were ligand-protein docking and virtual screening that were performed by some software and programs. The compound 1 and some positive controls act as ligand were subject binding to PrgQ, PrgX, PrgZ, and CcfA as proteins target, the ligands were free for blind docking. A framework was presented potency of phenolic compounds to inhibit the protein’s target from its affinity binding scores. Results It was found thatcompound 1 was potential to inhibit all of the tested protein and gave the highest binding affinity to PrgX (−9.2 kcal.mol −1 ; the site at Phe59B, Phe59B, Asn63A, and Asn63B residue) and PrgZ (−7.4 kcal.mol −1 ; the site at Leu4B, Thr65A, Thr82A. Gln81A, and Val5B residue). Conclusion It is proposed that compound 1 has a good activity to inhibit E. faecalis through its peptide pheromones in the QS system.

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Novel Small-molecule Antibacterials against Gram-positive Pathogens of Staphylococcus and Enterococcus Species

Cited by 9 publications

References 23 publications

A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

Pharmaceutical Approaches on Antimicrobial Resistance: Prospects and Challenges

<p>Antibacterial of Dibenzo-<em>p</em>-Dioxi-2,8-Dicarboxylic Acid Against Pathogenic Oral Bacteria <em>E. faecalis</em> ATCC 29212 Peptide Pheromones: Quorum Sensing of in vitro and in silico Study</p>

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