Antibiotic Substrate Selectivity of Pseudomonas aeruginosa MexY and MexB Efflux Systems Is Determined by a Goldilocks Affinity

Dey, Debayan; Kavanaugh, Logan G.; Conn, Graeme L.

doi:10.1128/aac.00496-20

Cited by 20 publications

(15 citation statements)

References 26 publications

(24 reference statements)

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“…MexB-Pa has five positively charged residues (3xK, 2xR, Table 7, orange) and only one negatively charged residue (1xD), while MexY-Pa harbors mainly negatively charged residues (3xE, 3xD, Table 7, green), with only one positively charged residue (1xK). These differences were also observed in computer simulations, where more charged residues are accounted for [102], and a recent study comparing the two pumps in more detail [101]. This significantly negatively charged DBP could explain why MexY-Pa has the ability to export aminoglycosides besides having a broad substrate range (possible by also having a hydrophobic pit), offering a different explanation than for AcrD-Ec.…”

Section: Differences Between Distal Binding Pockets Explain Aminoglycoside Selectivitymentioning

confidence: 82%

“…While the differences in the DBP (both residues and hydrophobicity) explain both aminoglycoside recognition and the inability to export many other drugs by AcrD-Ec, they do not explain a similar phenomenon between MexY-Pa and MexB-Pa [100]. These two pumps are phylogenetically closer to each other than AcrB-Ec and AcrD-Ec [15,100,101], and both show similar hydrophilicity in the DBP of around 26-27 kcal mol −1 (Table 7). MexB-Pa and MexY-Pa both have a broad substrate range (especially when compared to AcrD-Ec), including erythromycin, tetracycline, chloramphenicol and more.…”

Section: Differences Between Distal Binding Pockets Explain Aminoglycoside Selectivitymentioning

confidence: 99%

“…These three residues are implicated in monobactam (aztreonam) and anionic β-lactam (carbenicillin and sulbenicillin) selectivity in AcrD-Ec, and substitution of these residues in AcrB-Ec (Q569R/I626R/E673G) as a triple mutant adds or increases the efflux ability of AcrB-Ec for these three β-lactams [99], providing an explanation to why AcrD-Ec can export aztreonam, carbenicillin and sulbenicillin, while MexY-Pa and AcrB-Ec cannot (or only weakly) [99,100,105]. There are more differences between these efflux pumps, such as the ability of MexB-Pa to efflux imipenem, meropenem, carbenicillin and sulbenicillin, which is not recognized by MexY-Pa [101,105]. Perhaps the differences in charged and hydrophobic residues account for these specificities (Tables 5-7), as MexB-Pa does not have AcrD's Arg and Gly residues in the PBP.…”

Section: Specific Amino Acids In the Proximal Binding Pocket Explain β-Lactam Selectivitymentioning

confidence: 99%

“…As mentioned above, it would be interesting to determine the structure of phylogenetically distanced AcrB-Hi-like pumps to further understand the recognition determinants and pocket residues. Other differences besides residues in binding pockets (such as differences in the volume of the pockets, movements of loops, distances between loops, interactions with substrates to residues and the importance of water within the pockets and channels) between different pumps are investigated by molecular dynamics to try to explain specific differences between these pumps and their mechanisms (which cannot always be readily understood by only comparing the residues within the pockets) [96,101,102,108,109].…”

Section: Conserved Residues May Partly Explain Conserved Drug Specificitiesmentioning

confidence: 99%

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Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

Zwama

Nishino

2021

Antibiotics

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The rise in multidrug resistance (MDR) is one of the greatest threats to human health worldwide. MDR in bacterial pathogens is a major challenge in healthcare, as bacterial infections are becoming untreatable by commercially available antibiotics. One of the main causes of MDR is the over-expression of intrinsic and acquired multidrug efflux pumps, belonging to the resistance-nodulation-division (RND) superfamily, which can efflux a wide range of structurally different antibiotics. Besides over-expression, however, recent amino acid substitutions within the pumps themselves—causing an increased drug efflux efficiency—are causing additional worry. In this review, we take a closer look at clinically, environmentally and laboratory-evolved Gram-negative bacterial strains and their decreased drug sensitivity as a result of mutations directly in the RND-type pumps themselves (from Escherichia coli, Salmonella enterica, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Acinetobacter baumannii and Legionella pneumophila). We also focus on the evolution of the efflux pumps by comparing hundreds of efflux pumps to determine where conservation is concentrated and where differences in amino acids can shed light on the broad and even broadening drug recognition. Knowledge of conservation, as well as of novel gain-of-function efflux pump mutations, is essential for the development of novel antibiotics and efflux pump inhibitors.

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Section: Differences Between Distal Binding Pockets Explain Aminoglycoside Selectivitymentioning

confidence: 82%

Section: Differences Between Distal Binding Pockets Explain Aminoglycoside Selectivitymentioning

confidence: 99%

Section: Specific Amino Acids In the Proximal Binding Pocket Explain β-Lactam Selectivitymentioning

confidence: 99%

Section: Conserved Residues May Partly Explain Conserved Drug Specificitiesmentioning

confidence: 99%

See 2 more Smart Citations

Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time

Zwama

Nishino

2021

Antibiotics

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“…Docking grid size was determined based on the nucleic acid binding pocket volume and designed to completely cover all residues and centered symmetrically. Docking was performed using the virtual screening workflow of GLIDE (42) in Schrödinger Software, in HTVS mode and then for precision docking in SP mode as used in our previous studies (33,43).…”

Section: Virtual Screening Docking and Conformational Analysismentioning

confidence: 99%

Targeted redesign of suramin analogs for novel antimicrobial lead development

Dey

Ramakumar

Conn

2021

Preprint

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The emergence of new viral infections and drug resistant bacteria urgently necessitates expedient therapeutic development. Repurposing and redesign of existing drugs against different targets is one potential way in which to accelerate this process. Suramin was initially developed as a successful anti-parasitic drug, but has also shown promising antiviral and antibacterial activities. However, due to its high conformational flexibility and negative charge, suramin is considered quite promiscuous towards positively charged sites within nucleic acid binding proteins. Although some suramin analogs have been developed against specific targets, only limited structure activity relationship (SAR) studies were performed, and virtual screening has yet to be used to identify more specific inhibitor(s) based on its scaffold. Using available structures, we investigated suramin's target diversity, confirming that suramin preferentially binds to protein pockets which are both positively charged and enriched in aromatic or leucine residues. Further, suramin's high conformational flexibility allows adaptation to structurally diverse binding surfaces. From this platform, we developed a framework for structure- and docking-guided elaboration of suramin analog scaffolds using virtual screening of suramin and heparin analogs against a panel of diverse therapeutically relevant viral and bacterial protein targets. Use of this new framework to design potentially specific suramin analogs is exemplified using the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and nucleocapsid protein, identifying leads that might inhibit a wide range of coronaviruses. The approach presented here establishes a new computational framework for designing suramin analogs against different bacterial and viral targets and repurposing existing drugs for more specific inhibitory activity.

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