Identification of a Compound That Inhibits the Growth of Gram-Negative Bacteria by Blocking BamA–BamD Interaction

Li, Yan; Zhu, Xiaofan; Zhang, Jing; Lin, Yuan; You, Xuefu; Chen, Minghua; Wang, Yanchang; Zhu, Ning; Si, Shuyi

doi:10.3389/fmicb.2020.01252

Cited by 23 publications

(29 citation statements)

References 53 publications

(91 reference statements)

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“…ZipA (Compound 10b, Compound 4) 39,40 , LptA (Thanatin, IMB-881) 41,42 , LptD (JB-95) 43 , LolA (MAC13243) 44 , BamD (peptide and IMB-H4) 45,46 , MukB (Michellamine B and NSC176319) 47 , and TonB (multiple small bacteriostatic molecules and inhibitory compounds) [48][49][50] . None of these are currently developed for clinical use, however the presence of inhibitors indicates that the targets are druggable.…”

Section: Discussionmentioning

confidence: 99%

“…The selectivity of BamD and LptD can be further evaluated by future in vitro studies using known inhibitors that speci cally interfere with these proteins. 43,45,46 All in silico studies suffer from the drawback of cut-off criteria that may have little biological relevance. Stringent cut-off values potentially exclude valuable drug targets while loose criteria may result in an unmanageable list of targets.…”

Section: Discussionmentioning

confidence: 99%

“…Thanatin has been shown to possess antimicrobial activity against several Gram-negative bacteria beyond E. coli, including K. pneumoniae, Salmonella typhimurium and Enterobacter cloacae 41 . IMB-H4 was also able to inhibit growth in K. pneumoniae, P. aeruginosa and A. baumannii 46 . NSC176319 was found to be active against S. aureus and permeabilised P. aeruginosa and A. baumannii 47 .…”

Section: Existence Of Known Inhibitorsmentioning

confidence: 97%

“…compound IMB-881 blocks the interaction between LptA and LptC 42 ; JB-95 inhibits b-barrel proteins including LptD 43 ; MAC13243 inhibits LolA 44 ; BamD is inhibited by an inhibitory peptide 45 while the compound IMB-H4 has been shown to block BamA-BamD interaction 46 , and MukB is inhibited by the small molecules Michellamine B and NSC260594 47 . Finally, multiple inhibitory compounds targeting TonB have been identi ed [48][49][50] .…”

Section: Existence Of Known Inhibitorsmentioning

confidence: 99%

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In Silico Prediction and Prioritisation of Novel Selective Antimicrobial Drug Targets in Escherichia Coli

Frisinger

Jana

Donadio³

et al. 2021

Preprint

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Treatment of infections caused by Escherichia coli and other Enterobacteriaceae often requires broad-spectrum antimicrobials, which cause perturbations of the gut microbiota (dysbiosis). Novel antimicrobial drugs interfering with pathogen-specific targets would minimize the risk of such dysbiosis. Here, we employed an in silico approach to identify essential proteins in E. coli, including pathogenic ST131, that are either absent or have low homology to humans and beneficial taxa of the gut microbiota. We identified 37 potential new targets with little or no homology to the proteomes seven taxa representative of the healthy gut microbiota. The suitability of these proteins as drug targets was further analysed through essentiality and conservation in the closely related pathogen Klebsiella pneumoniae. None of them are targets of commercially used antibiotics. Eighteen proteins are involved in four functionally connected essential biological processes (replication, chromosome segregation, cell division, and outer membrane biogenesis). Our results indicate that it may be possible to selectively interfere with essential biological processes in Enterobacteriaceae that are absent or mediated by unrelated proteins in beneficial bacterial taxa residing in the gut. The identified targets can be used to discover antimicrobial drugs that are effective against these opportunistic pathogens with a decreased potential of causing dysbiosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Existence Of Known Inhibitorsmentioning

confidence: 97%

Section: Existence Of Known Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

In Silico Prediction and Prioritisation of Novel Selective Antimicrobial Drug Targets in Escherichia Coli

Frisinger

Jana

Donadio³

et al. 2021

Preprint

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“…95,96 A number of compounds have been proposed to target BamA or BamD, resulting in OM structure disruption. [97][98][99][100][101][102][103] While the mechanism of action of certain molecules is not clear, two in particular have been identified as targeting the PPI BamA-BamD.…”

Section: Targeting Outer Membrane Protein Complexesmentioning

confidence: 99%

Modulators of protein–protein interactions as antimicrobial agents

et al. 2021

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ATP‐independent assembly machinery of bacterial outer membranes: BAM complex structure and function set the stage for next‐generation therapeutics

George,

Patil,

Mahalakshmi

2024

Protein Science

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Diderm bacteria employ β‐barrel outer membrane proteins (OMPs) as their first line of communication with their environment. These OMPs are assembled efficiently in the asymmetric outer membrane by the β‐Barrel Assembly Machinery (BAM). The multi‐subunit BAM complex comprises the transmembrane OMP BamA as its functional subunit, with associated lipoproteins (e.g., BamB/C/D/E/F, RmpM) varying across phyla and performing different regulatory roles. The ability of BAM complex to recognize and fold OM β‐barrels of diverse sizes, and reproducibly execute their membrane insertion, is independent of electrochemical energy. Recent atomic structures, which captured BAM–substrate complexes, show the assembly function of BamA can be tailored, with different substrate types exhibiting different folding mechanisms. Here, we highlight common and unique features of its interactome. We discuss how this conserved protein complex has evolved the ability to effectively achieve the directed assembly of diverse OMPs of wide‐ranging sizes (8–36 β‐stranded monomers). Additionally, we discuss how darobactin—the first natural membrane protein inhibitor of Gram‐negative bacteria identified in over five decades—selectively targets and specifically inhibits BamA. We conclude by deliberating how a detailed deduction of BAM complex—associated regulation of OMP biogenesis and OM remodeling will open avenues for the identification and development of effective next‐generation therapeutics against Gram‐negative pathogens.

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Identification of a Compound That Inhibits the Growth of Gram-Negative Bacteria by Blocking BamA–BamD Interaction

Cited by 23 publications

References 53 publications

In Silico Prediction and Prioritisation of Novel Selective Antimicrobial Drug Targets in Escherichia Coli

In Silico Prediction and Prioritisation of Novel Selective Antimicrobial Drug Targets in Escherichia Coli

Modulators of protein–protein interactions as antimicrobial agents

ATP‐independent assembly machinery of bacterial outer membranes: BAM complex structure and function set the stage for next‐generation therapeutics

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