Resistance-nodulation-cell division superfamily

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RND permease superfamily
Crystallized AcrB HAE-RND efflux protein.jpg
Crystallized AcrB: An HAE-RND subclass protein involved in drug and amphiphilic efflux
Identifiers
SymbolRND_Permease
Pfam clan CL0322
ECOD 5067.1.1
TCDB 2.A.6
OPM superfamily 16
OPM protein 2gif

Resistance-nodulation-division (RND) family transporters are a category of bacterial efflux pumps, especially identified in Gram-negative bacteria and located in the cytoplasmic membrane, that actively transport substrates. The RND superfamily includes seven families: the heavy metal efflux (HME), the hydrophobe/amphiphile efflux-1 (gram-negative bacteria), the nodulation factor exporter family (NFE), the SecDF protein-secretion accessory protein family, the hydrophobe/amphiphile efflux-2 family, the eukaryotic sterol homeostasis family, and the hydrophobe/amphiphile efflux-3 family. [1] These RND systems are involved in maintaining homeostasis of the cell, removal of toxic compounds, and export of virulence determinants. [2] They have a broad substrate spectrum and can lead to the diminished activity of unrelated drug classes if over-expressed. The first reports of drug resistant bacterial infections were reported in the 1940s after the first mass production of antibiotics. [3] Most of the RND superfamily transport systems are made of large polypeptide chains. [4] RND proteins exist primarily in gram-negative bacteria but can also be found in gram-positive bacteria, archaea, and eukaryotes.

Contents

Function

The RND protein dictates the substrate for the completed transport systems including: metal ions, xenobiotics or drugs. Transport of hydrophobic and amphiphilic compounds are carried out by the HAE-RND subfamily. While the efflux of heavy metals are preformed HME-RND. [5]

Triparitate Complex Model: RND inner-membrane protein, outer-membrane fusion protein, & periplasmic adaptor protein. Triparitate Complex.jpg
Triparitate Complex Model: RND inner-membrane protein, outer-membrane fusion protein, & periplasmic adaptor protein.

Mechanism and structure

Crystallized CusA: HAE-RND subclass protein RND protein CusA.jpg
Crystallized CusA: HAE-RND subclass protein

RND proteins are large and can include more than 1000 amino acid residues. They are generally composed of two homologous subunits (suggesting they arose as a result of an intragenic tandem duplication event that occurred in the primordial system prior to divergence of the family members) each containing a periplasmic loop adjacent to 12 transmembrane helices. Of the twelve helices there is a single transmembrane spanner (TMS) at the N-terminus followed by a large extracytoplasmic domain, then six additional TMSs, a second large extracytoplasmic domain, and five final C-terminal TMSs. TM4 governs the specificity for a particular substrate in a given RND protein. Therefore, TM4 can be an indicator for RND specificity without explicit knowledge of the remainder of the protein. [6]

RND pumps are the cytoplasmic residing portion of a complete tripartite complex (Fig. 1) which spreads across the outer-membrane and the inner membrane of gram-negative bacteria, also commonly referred to as the CBA efflux system. The RND protein associates with an outer membrane channel and a periplasmic adaptor protein, and the association of all three proteins allows the system to export substrates into the external medium, providing a huge advantage for the bacteria. [7]

The CusA protein, a HME-RND member transporter, was able to be crystallized providing valuable structural information of HME-RND pumps. CusA exists as a homotrimer with each unit consisting of 12 transmembrane helices (TM1-TM12). The periplasmic domain consists of two helices, TM2 and TM8. In addition, the periplasmic domain is made up of six subdomains, PN1, PN2, PC1, PC2, DN, DC, which form a central pore and a dock domain. The central pore is formed by PN1, PN2, PC1, PC2, and together stabilize the trimeric organization of the homotrimer. [8]

Metal ion efflux (HME-RND)

The HME-RND family functions as the central protein pump in metal ion efflux powered by a proton-substrate antiport. The family includes pumps which export monovalent metals—the Cus system, and pumps which export divalent metals—the Czc system. [5]

Heavy metal resistance by the RND family was first discovered in R. metallidurans through the CzcA and later the CnrA protein. The best characterized RND proteins include CzcCBA (Cd2+, Zn2+, and Co2+), CnrCBA (Ni2+ and Co2+), and NccCBA (Ni2+, Co2+ and Cd2+) in Cupriavidus, Czr (Cd2+ and Zn2+ resistance) in Pseudomonas aeruginosa, and Czn (Cd2+, Zn2+, and Ni2+ resistance) in Helicobacter pylori. [9] It has been proposed that metal-ion efflux occurs from the cytoplasm and periplasm based on the location of multiple substrate binding sites on the RND protein. [6]

CznCBA

The Czn system maintains homeostasis of Cadmium, Zinc, and Nickel resistance; it is involved in Urease modulation, and gastric colonization by H. pylori . The CznC and CznA proteins play the dominating role in nickel homeostasis. [10]

CzcCBA

Czc confers resistance to Cobalt, Zinc, and Cadmium. The CzcCBA operon includes: CzcA (the RND family specific protein), the membrane fusion protein (MFP) CzcB, and the outer membrane factor protein (OMF) CzcC, all of which form the active tripartite complex, and the czcoperon. Expression of the operon is regulated through metal ions. [6]

Drug resistance (HAE-RND)

The RND family plays an important role in producing intrinsic and elevated multi-drug resistance in gram-negative bacteria. The export of amphiphilic and hydrophobic substrates is governed by the HAE-RND family. In E. coli five RND pumps have been specifically identified: AcrAB, AcrAD, AcrEF, MdtEF, and MdtAB. Although it is not clear how the tripartite complex works in bacteria two mechanisms have been proposed: Adaptor Bridging Model and Adaptor Wrapping Model.[ citation needed ]

HAE-RNDs involvement in the detoxification and exportation of organic substrates allowed for recent characterization of specific pumps due to their increasing medical relevance. Half of the antibiotic resistance demonstrated in in vivo hospital strains of Pseudomonas aeruginosa was attributed to RND efflux proteins. P. aeruginosa contain 13 RND transport systems, including one HME-RND and the remaining HAE-RNDs. Among the best identified are the Mex proteins: MexB, MexD, and MexF, which detoxify organic substances. It is proposed that the MexB systems demonstrates substrate specificity for beta-lactams; while the MexD-system expresses specificity for cepheme compounds. [6]

E. coli – AcrB

In E. coli multi-drug resistance develops from a variety of mechanisms. Particularly concerning is the ability of efflux mechanisms to confer broad-spectrum resistance. RND efflux pumps provide extrusion for a range of compounds. Five protein transporters in E. coli cells that belong to the HAE-RND subfamily have been classified, [11] including the multi-drug efflux protein AcrB, the outer membrane protein TolC and the periplasmic adaptor protein AcrA. [12] The TolC and AcrA proteins are also utilized in the tripartite complex in other identified RND efflux proteins. [11] The AcrAB-TolC efflux system is responsible for the efflux of antimicrobial drugs like penicillin G, cloxacillin, nafcillin, macrolides, novobiocin, linezolid, and fusidic acid antibiotics. Other substrates include dyes, detergents, some organic solvents, and steroid hormones. The ways in which the lipophilic domains of the substrate and the RND pumps is not completely defined.[ citation needed ]

The crystallized AcrB protein, provides insight into the mechanism of action of HAE-RND proteins, and other RND family proteins. [6]

Multidrug transport (Mdt) efflux

Mdt(A) is an efflux pump that confers resistance to a variety of drugs. It is expressed in L. lactis, E. coli and various other bacteria. Unlike other RND proteins Mdt(A) contains a putative ATP-binding site and two C-motifs conserved in its fifth TMS. Mdt is effective at providing the bacteria with resistance to tetracycline, chloramphenicol, lincosamides and streptomycin. The source of energy for active efflux by Mdt(A) is currently unknown. [13]

Related Research Articles

<span class="mw-page-title-main">Transmembrane protein</span> Protein spanning across a biological membrane

A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents.

The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the periplasmic space in Gram-negative bacteria. Using cryo-electron microscopy it has been found that a much smaller periplasmic space is also present in Gram-positive bacteria, between cell wall and the plasma membrane. The periplasm may constitute up to 40% of the total cell volume of gram-negative bacteria, but is a much smaller percentage in gram-positive bacteria.

<span class="mw-page-title-main">ABC transporter</span> Gene family

The ABC transporters, ATP synthase (ATP)-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.

<span class="mw-page-title-main">Bacterial outer membrane</span> Plasma membrane found in gram-negative bacteria

The bacterial outer membrane is found in gram-negative bacteria. Gram-negative bacteria form two lipid bilayers in their cell envelopes - an inner membrane (IM) that encapsulates the cytoplasm, and an outer membrane (OM) that encapsulates the periplasm.

<span class="mw-page-title-main">Efflux pump</span> Protein complexes that move compounds, generally toxic, out of bacterial cells

An efflux pump is an active transporter in cells that moves out unwanted material. Efflux pumps are an important component in bacteria in their ability to remove antibiotics. The efflux could also be the movement of heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals, bacterial metabolites and neurotransmitters. All microorganisms, with a few exceptions, have highly conserved DNA sequences in their genome that encode efflux pumps. Efflux pumps actively move substances out of a microorganism, in a process known as active efflux, which is a vital part of xenobiotic metabolism. This active efflux mechanism is responsible for various types of resistance to bacterial pathogens within bacterial species - the most concerning being antibiotic resistance because microorganisms can have adapted efflux pumps to divert toxins out of the cytoplasm and into extracellular media.

<span class="mw-page-title-main">Cross-resistance</span> Chemicals stop working at the same time

Cross-resistance is when something develops resistance to several substances that have a similar mechanism of action. For example, if a certain type of bacteria develops resistance to one antibiotic, that bacteria will also have resistance to several other antibiotics that target the same protein or use the same route to get into the bacterium. A real example of cross-resistance occurred for nalidixic acid and ciprofloxacin, which are both quinolone antibiotics. When bacteria developed resistance to ciprofloxacin, they also developed resistance to nalidixic acid because both drugs inhibit topoisomerase, a key enzyme in DNA replication. Due to cross-resistance, antimicrobial treatments like phage therapy can quickly lose their efficacy against bacteria. This makes cross-resistance an important consideration in designing evolutionary therapies.

<span class="mw-page-title-main">Outer membrane efflux protein</span>

The outer membrane efflux protein is a protein family member that forms trimeric (three-piece) channels allowing the export of a variety of substrates in gram-negative bacteria. Each efflux protein is composed of two repeats. The trimeric channel is composed of a 12-stranded beta-barrel that spans the outer membrane, and a long tail helical barrel that spans the periplasm.

<span class="mw-page-title-main">Multidrug and toxin extrusion protein 1</span> Protein-coding gene in the species Homo sapiens

Multidrug and toxin extrusion protein 1 (MATE1), also known as solute carrier family 47 member 1, is a protein that in humans is encoded by the SLC47A1 gene. SLC47A1 belongs to the MATE family of transporters that are found in bacteria, archaea and eukaryotes.

<span class="mw-page-title-main">Multidrug and toxin extrusion protein 2</span> Protein-coding gene in the species Homo sapiens

Multidrug and toxin extrusion protein 2 is a protein which in humans is encoded by the SLC47A2 gene.

Multi-antimicrobial extrusion protein (MATE) also known as multidrug and toxin extrusion or multidrug and toxic compound extrusion is a family of proteins which function as drug/sodium or proton antiporters.

SmeT is a transcriptional repressor protein of 24.6 kDa, found in the pathogenic bacteria Stenotrophomonas maltophilia. SmeT is responsible for the regulation of the Multidrug Resistance (MDR) efflux pump, SmeDEF, that gives the bacteria resistance to several antibiotics including macrolides, TMP/SMX, tetracycline, chloramphenicol, quinolones and erythromycin. SmeT is encoded 223 bp upstream of SmeDEF, with just 56 base pairs between their transcription start sites and an overlapping region between the promoters. The production of the SmeT protein downregulates its own transcription, along with that of the efflux pump by sterically hindering the binding of RNA Polymerase to the DNA. SmeDEF was the first MDR pump discovered in the S. maltophilia species. The pump is named by its different parts: SmeE, the transporter itself that spans the plasma membrane, SmeF, the protein on the outer portion of the membrane, and SmeD, a membrane fusion protein. On general purpose media and no selectors, the genes for MDR pumps are typically not expressed, and the repressor is found bound to the DNA. In fact, mutations in SmeT that lead to overexpression of SmeDEF can pose fitness challenges to the bacteria. However, this overexpression has been identified in the bacterium and may pose a threat to our health.

<span class="mw-page-title-main">Plasmid-mediated resistance</span> Antibiotic resistance caused by a plasmid

Plasmid-mediated resistance is the transfer of antibiotic resistance genes which are carried on plasmids. Plasmids possess mechanisms that ensure their independent replication as well as those that regulate their replication number and guarantee stable inheritance during cell division. By the conjugation process, they can stimulate lateral transfer between bacteria from various genera and kingdoms. Numerous plasmids contain addiction-inducing systems that are typically based on toxin-antitoxin factors and capable of killing daughter cells that don't inherit the plasmid during cell division. Plasmids often carry multiple antibiotic resistance genes, contributing to the spread of multidrug-resistance (MDR). Antibiotic resistance mediated by MDR plasmids severely limits the treatment options for the infections caused by Gram-negative bacteria, especially family Enterobacteriaceae. The global spread of MDR plasmids has been enhanced by selective pressure from antimicrobial medications used in medical facilities and when raising animals for food.

Cation diffusion facilitators (CDFs) are transmembrane proteins that provide tolerance of cells to divalent metal ions, such as cadmium, zinc, and cobalt. These proteins are considered to be efflux pumps that remove these divalent metal ions from cells. However, some members of the CDF superfamily are implicated in ion uptake. All members of the CDF family possess six putative transmembrane spanners with strongest conservation in the four N-terminal spanners. The Cation Diffusion Facilitator (CDF) Superfamily includes the following families:

<span class="mw-page-title-main">Acriflavine resistance protein family</span>

The Escherichia coliAcriflavine resistance encode a multi-drug efflux system that is believed to protect the bacterium against hydrophobic inhibitors. The E. coli AcrB protein is a transporter that is energized by proton-motive force and that shows the widest substrate specificity among all known multidrug pumps, ranging from most of the currently used antibiotics, disinfectants, dyes, and detergents to simple solvents.

The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily is a group of integral membrane protein families. The MOP flippase superfamily includes twelve distantly related families, six for which functional data are available:

  1. One ubiquitous family (MATE) specific for drugs - (TC# 2.A.66.1) The Multi Antimicrobial Extrusion (MATE) Family
  2. One (PST) specific for polysaccharides and/or their lipid-linked precursors in prokaryotes - (TC# 2.A.66.2) The Polysaccharide Transport (PST) Family
  3. One (OLF) specific for lipid-linked oligosaccharide precursors of glycoproteins in eukaryotes - (TC# 2.A.66.3) The Oligosaccharidyl-lipid Flippase (OLF) Family
  4. One (MVF) lipid-peptidoglycan precursor flippase involved in cell wall biosynthesis - (TC# 2.A.66.4) The Mouse Virulence Factor (MVF) Family
  5. One (AgnG) which includes a single functionally characterized member that extrudes the antibiotic, Agrocin 84 - (TC# 2.A.66.5) The Agrocin 84 Antibiotic Exporter (AgnG) Family
  6. And finally, one (Ank) that shuttles inorganic pyrophosphate (PPi) - (TC# 2.A.66.9) The Progressive Ankylosis (Ank) Family

Arsenite resistance (Ars) efflux pumps of bacteria may consist of two proteins, ArsB and ArsA, or of one protein. ArsA proteins have two ATP binding domains and probably arose by a tandem gene duplication event. ArsB proteins all possess twelve transmembrane spanners and may also have arisen by a tandem gene duplication event. Structurally, the Ars pumps resemble ABC-type efflux pumps, but there is no significant sequence similarity between the Ars and ABC pumps. When only ArsB is present, the system operates by a pmf-dependent mechanism, and consequently belongs in TC subclass 2.A. When ArsA is also present, ATP hydrolysis drives efflux, and consequently the system belongs in TC subclass 3.A. ArsB therefore appears twice in the TC system but ArsA appears only once. These pumps actively expel both arsenite and antimonite.

The 6TMS Neutral Amino Acid Transporter (NAAT) Family is a family of transporters belonging to the Lysine Exporter (LysE) Superfamily. Homologues are found in numerous Gram-negative and Gram-positive bacteria including many human pathogens. Several archaea also encode MarC homologues. Some of these organisms have 2 or more paralogues. Most of these proteins are of about the same size although a few are larger. They exhibit 6 putative TMSs. A representative list of members belonging to the NAAT family can be found in the Transporter Classification Database.

Multidrug resistance pumps also known Multidrug efflux pumps are a type of efflux pump and P-glycoprotein. MDR pumps in the cell membrane extrudes many foreign substances out of the cells and some pumps can have a broad specificity. MDR pumps exist in animals, fungi, and bacteria and likely evolved as a defense mechanism against harmful substances. There are seven families of MDRs and are grouped by homology, energy source, and overall structure.

<span class="mw-page-title-main">Colin Hughes (microbiologist)</span> British microbiologist (born 1953)

Colin Hughes PhD ScD FLSW is a British microbiologist who has worked in the areas of bacterial virulence, motility and antibiotic resistance. He is Emeritus Professor of Microbiology at the University of Cambridge, Fellow of Trinity College Cambridge, and Fellow of the Learned Society of Wales.

<span class="mw-page-title-main">Multidrug-resistant bacteria</span>

Multidrug-resistant bacteria are bacteria that are resistant to three or more classes of antimicrobial drugs. MDR bacteria have seen an increase in prevalence in recent years and pose serious risks to public health. MDR bacteria can be broken into 3 main categories: Gram-positive, Gram-negative, and other (acid-stain). These bacteria employ various adaptations to avoid or mitigate the damage done by antimicrobials. With increased access to modern medicine there has been a sharp increase in the amount of antibiotics consumed. Given the abundant use of antibiotics there has been a considerable increase in the evolution of antimicrobial resistance factors, now outpacing the development of new antibiotics.

References

  1. ↑ Tseng TT, Gratwick KS, Kollman J, Park D, Nies DH, Goffeau A, Saier MH (August 1999). "The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins". Journal of Molecular Microbiology and Biotechnology. 1 (1): 107–25. PMID   10941792.
  2. ↑ Coyne S, Rosenfeld N, Lambert T, Courvalin P, Périchon B (October 2010). "Overexpression of resistance-nodulation-cell division pump AdeFGH confers multidrug resistance in Acinetobacter baumannii". Antimicrobial Agents and Chemotherapy. 54 (10): 4389–93. doi:10.1128/AAC.00155-10. PMC   2944555 . PMID   20696879.
  3. ↑ Routh, Mathew David, "Structure, function, and regulation of multidrug export proteins among the RND superfamily in Gram-negative bacteria" (2010). Graduate Theses and Dissertations. Paper 11401. http://lib.dr.iastate.edu/etd/11401
  4. ↑ "2.A.6 The Resistance-Nodulation-Cell Division (RND) Superfamily". Transporter Classification Database.
  5. 1 2 Moraleda-Muñoz A, Pérez J, Extremera AL, Muñoz-Dorado J (September 2010). "Differential regulation of six heavy metal efflux systems in the response of Myxococcus xanthus to copper". Applied and Environmental Microbiology. 76 (18): 6069–76. Bibcode:2010ApEnM..76.6069M. doi:10.1128/AEM.00753-10. PMC   2937488 . PMID   20562277.
  6. 1 2 3 4 5 Nies DH (June 2003). "Efflux-mediated heavy metal resistance in prokaryotes". FEMS Microbiology Reviews. 27 (2–3): 313–39. doi: 10.1016/s0168-6445(03)00048-2 . PMID   12829273.
  7. ↑ Nikaido H (2011). "Structure and mechanism of RND-type multidrug efflux pumps". Advances in Enzymology and Related Areas of Molecular Biology. Vol. 77. Wiley. pp. 1–60. doi:10.1002/9780470920541.ch1. ISBN   9780470920541. PMC   3122131 . PMID   21692366.
  8. ↑ Long F, Su CC, Zimmermann MT, Boyken SE, Rajashankar KR, Jernigan RL, Yu EW (September 2010). "Crystal structures of the CusA efflux pump suggest methionine-mediated metal transport". Nature. 467 (7314): 484–8. Bibcode:2010Natur.467..484L. doi:10.1038/nature09395. PMC   2946090 . PMID   20865003.
  9. ↑ Valencia EY, Braz VS, Guzzo C, Marques MV (April 2013). "Two RND proteins involved in heavy metal efflux in Caulobacter crescentus belong to separate clusters within proteobacteria". BMC Microbiology. 13: 79. doi: 10.1186/1471-2180-13-79 . PMC   3637150 . PMID   23578014.
  10. ↑ Stähler FN, Odenbreit S, Haas R, Wilrich J, Van Vliet AH, Kusters JG, Kist M, Bereswill S (July 2006). "The novel Helicobacter pylori CznABC metal efflux pump is required for cadmium, zinc, and nickel resistance, urease modulation, and gastric colonization". Infection and Immunity. 74 (7): 3845–52. doi:10.1128/IAI.02025-05. PMC   1489693 . PMID   16790756.
  11. 1 2 Anes J, McCusker MP, Fanning S, Martins M (2015). "The ins and outs of RND efflux pumps in Escherichia coli". Frontiers in Microbiology. 6: 587. doi: 10.3389/fmicb.2015.00587 . PMC   4462101 . PMID   26113845.
  12. ↑ Nikaido H, Takatsuka Y (May 2009). "Mechanisms of RND multidrug efflux pumps". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1794 (5): 769–81. doi:10.1016/j.bbapap.2008.10.004. PMC   2696896 . PMID   19026770.
  13. ↑ Perreten V, Schwarz FV, Teuber M, Levy SB (April 2001). "Mdt(A), a new efflux protein conferring multiple antibiotic resistance in Lactococcus lactis and Escherichia coli". Antimicrobial Agents and Chemotherapy. 45 (4): 1109–14. doi:10.1128/AAC.45.4.1109-1114.2001. PMC   90432 . PMID   11257023.
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