Serratia marcescens' different drug resistant efflux pumps: Difference between revisions

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=Introduction=
=Introduction=


"Serratia marcescens" is a gram-negative bacillus bacterium classified as a member of the [http://en.wikipedia.org/wiki/Enterobacteriaceae Enterobacteriaceae] family. It is an [http://www.biology-online.org/dictionary/Opportunistic_pathogen opportunistic pathogen] and has been the cause of [http://www.healthline.com/galecontent/nosocomial-infections nosocomial infections] for the past two decades[[#References|[5]]]. S. marcescens is motile and a facultative anaerobe and is well known for its pink pigmented colonies which are commonly seen on the walls of bathtubs or tiles where soap residue is usually found. Many infections caused by "S. marcescens" are difficult to treat due to antibiotic resistance that the bacterium has developed[[#References|[11]]]. Studies have shown that S. marcescens have multidrug resistance due to the efflux pumps that it maintains[[#References|[3]]].
''Serratia marcescens'' is a gram-negative bacillus bacterium classified as a member of the [http://en.wikipedia.org/wiki/Enterobacteriaceae Enterobacteriaceae] family. It is an [http://www.biology-online.org/dictionary/Opportunistic_pathogen opportunistic pathogen] and has been the cause of [http://www.healthline.com/galecontent/nosocomial-infections nosocomial infections] for the past two decades[[#References|[5]]]. ''S. marcescens'' is motile and a facultative anaerobe and is well known for its pink pigmented colonies which are commonly seen on the walls of bathtubs or tiles where soap residue is usually found. Many infections caused by ''S. marcescens'' are difficult to treat due to antibiotic resistance that the bacterium has developed[[#References|[11]]]. Studies have shown that ''S. marcescens'' have multidrug resistance due to the efflux pumps that it maintains[[#References|[3]]].


[[File:260px-Serratia marcescens.jpg|300px|thumb|center| ''Serratia marcescens''. Retrieved from http://commons.wikimedia.org/wiki/File:Serratia_marcescens.jpg]]


=Efflux Pumps=
[http://en.wikipedia.org/wiki/Efflux_(microbiology) Efflux] pumps in bacterial cells are transport proteins that contribute to the expulsion of toxic substrates from inside the cell to the environment[[#References|[12]]]. Such toxic substrates such as [http://www.drugs.com/erythromycin.html erythromycin], [http://en.wikipedia.org/wiki/Streptomycin streptomycin] and [http://en.wikipedia.org/wiki/Norfloxacin norflaxin], are clinically developed antibiotics that target the cell’s physiological processes. There are five major efflux pumps found in bacterial cells: MF (major facilitator), MATE (multidrug and toxic efflux), RND (resistance-nodulation-division), SMR (small multidrug resistance) and ABC (ATP-binding cassette)[[#References|[12]]]. ''S. marcescens'' is found to have four of the five major efflux pumps. S. marcescens has been characterized to express three RND-type7 and one from the MF, SMR and ABC-type efflux pumps. Efflux pumps play an important role in the drug resistance capabilities of bacteria including ''Escherichia coli'', especially in ''S. marcescens''.


=Current Species=
[[File:Efflux pumps.jpg|600px|thumb|center| Figure 2. Different know bacterial efflux pumps in gram-negative bacteria. Shown in the diagram are the flow of substrates (drugs) and energy source for the different efflux pumps.]]




=''Serratia marcescens''' Efflux Pumps=
There are six efflux pumps found in ''S. marcescens'' that have been characterized:


=Morphology=
===SdeAB (''Serratia’s'' drug efflux)===
It is an RND-type (resistance-nodulation-cell division) efflux pump with genes that code for both an MF and RND-type efflux pumps. It uses a proton gradient as an energy source and consists of a tripartite complex protein. It mostly pumps out [http://en.wikipedia.org/wiki/Quinolone fluoroquinolones] and is known to be the major fluoroquinolone pump in ''S. marcescens''.[[#References|[6]]],[[#References|[7]]]


The members of the ''Ignicoccus''  genus are motile irregular coccoid cells that range in diameter from 1 to 3 µm. The motility observed is due to the presence of flagella, but unfortunately the polarity of the flagella is not yet fully elucidated. They are known to have an outer-membrane but no [http://en.wikipedia.org/wiki/S-layer S-layer]. This is a novel characteristic for these [http://en.wikipedia.org/wiki/Archaea Archaea] because''Ignicoccus'' are the only known Archaea that have been shown to possess an outer-membrane[[#References|[2]]] [[#References|[10]]] .
===SdeCDE===
It is an RND-type efflux pumps that is a combination of one MFP (membrane fusion protein for sdeC) and two RND (sdeDE) pump transporters which uses the proton gradient for energy. This type of efflux pump also exhibits a tripartite complex and is found to have restrictive selectivity only to [http://en.wikipedia.org/wiki/Novobiocin novobiocin]1. It is also found to be the third RND-type pump to be characterized for ''S. marcescens''.[[#References|[1]]]


[[File:Huber-abb2.jpg|300px|thumb|left| Ultrathin section of an ''Ignicoccus hospitalis'' cell.]]
===SdeXY===
It is an RND-type efflux pump which uses a proton gradient as an energy source. It is composed of two components to make up the complex: SdeX, a hydrophilic protein found to be an MFP; SdeY, an integral protein that has many hydrophobic residues and many [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] domains. It is resistant to a wide variety of antimicrobial agents and was the first RND-type to be characterized in ''S. marcescens''[[#References|[4]]].


===SsmE (''Serratia’s'' small multidrug resistance)===
It is an SMR-type (small multidrug resistance) efflux pumps that is energy-dependent and works as a substrate/H+ [http://en.wikipedia.org/wiki/Antiporter antiporter] and expels substrates out of the cell. It is composed of four transmembrane domains that span the cell membrane. It is particularly resistant to [http://en.wikipedia.org/wiki/Ethidium_bromide ethidium bromide] and [http://en.wikipedia.org/wiki/Acriflavinium_chloride acriflavine] and is known to be an ethidium efflux[[#References|[9]]].


==Outer-Membrane==
===SmfY (''Serratia’s'' major facilitator)===
It is a member of the MF (major facilitator) superfamily transporters that is an energy-dependent efflux pump that contains numerous hydrophobic residues. These residues are long enough to extend around the cell membrane. It is commonly resistant to a known antiseptic called [http://en.wikipedia.org/wiki/Benzalkonium_chloride benzalkonium chloride]. This is the very first MF-type multidrug efflux pump to be discovered[[#References|[10]]].


The outer-membrane of ''Ignicoccus''  species was found to be composed of various derivatives of the typical lipid [http://en.wikipedia.org/wiki/Archaeol archaeol], including the derivative known as [http://en.wikipedia.org/wiki/Caldarchaeol caldarchaeol] [[#References|[5]]] . The outer-membrane is dominated by a pore composed of the Imp1227 protein (''Ignicoccus'' outer membrane protein 1227). The Imp1227 protein forms a large nonamer ring with a predicted pore size of 2nm[[#References|[7]]] .
===SmdAB (for Serratia MultiDrug resistance)===
It is an ABC-type (ATP-binding cassette) multidrug efflux pumps which utilizes ATP as an energy source. It is the very first report of a heterodimer that is seen working in a gram-negative bacterium. It is composed of six transmembrane segments and has hydrophilic segments which contain recognized-binding domains. It is found to be resistant to many cytotoxic agents like norflaxin or tetracycline. This was the very first ABC-type multidrug efflux pump to be characterized in ''S. marcescens''[[#References|[8]]].


=Metabolism=


''Ignicoccus'' species are [http://en.wikipedia.org/wiki/Chemolithoautotroph chemolithoautotrophs] that use molecular hydrogen as the inorganic electron donor and elemental sulphur as the inorganic terminal electron acceptor[[#References|[1]]] . The reduction of the elemental sulphur results in the production of hydrogen sulphide gas.  
=Impact of Multidrug Resistant Efflux Pumps=
The number of patients in recent years has greatly increased due to the drug resistance of ''S. marcescens''[[#References|[3]]]. Life threatening infections such as [http://www.nlm.nih.gov/medlineplus/ency/article/001355.htm septicemia], [http://en.wikipedia.org/wiki/Endocarditis endocarditis] and [http://en.wikipedia.org/wiki/Meningitis meningitis] are only some of the infections caused by ''S. marcescens''[[#References|[11]]]. Due to the evolutionary adaptations of ''S. marcescens'' in drug resistance, such infections stated are extremely difficult to treat. With the characterization and the further studies of the different multidrug efflux pumps, we are able to understand the mechanisms and the distinct antibiotics that ''S. marcescens'' is resistant to which is key in developing inhibitors and other mechanisms to hinder their function[[#References|[11]]].


''Ignicoccus'' are autotrophs in that they fix their own carbon dioxide into organic molecules. The carbon dioxide fixation process they use is a novel process called [http://www.pnas.org/content/105/22/7851.full a dicarboxylate/4-hydroxybutyrate autotrophic carbon assimilation cycle] that involves 14 different enzymes[[#References|[8]]] .
[[File:Serratia efflux pump.jpg|350px|thumb|right| Figure 3. ''S. marcescens'' known to be pretty “bad-ass” towards multiple antibiotics. It regulates its genes to express more efflux pumps due to an increase in antibiotics in the environment.]]


Members of the ''Ignicoccus''  genus are able to use ammonium as a nitrogen source.


==Growth Conditions==
=Treatment=
''S. marcescens'' has increased stress in society due to its emerging resistance mechanisms that make its efflux pumps resistant to various antibiotics. Various mechanisms are formulated like controlling the membrane permeability or the production of innovative molecules which are insensitive to these resistant mechanisms for effective treatment[[#References|[2]]]. Recent studies have formulated different strategies in order to elude the drug resistance efflux pumps by doing the following: generating better molecular designs to bypass the efflux activity, directly decreasing the effectiveness of the cell membrane with a channel blocker to induce “traffic jams”, and by blocking the efflux capacity by altering the function of the efflux pump in the bacterial cell wall with inhibition mechanisms[[#References|[2]]].


Because members of the ''Ignicoccus''  genus are [http://en.wikipedia.org/wiki/Hyperthermophile hyperthermophiles] and obligate anaerobes, it is not surprising that their growth conditions are very complex. They are grown in a liquid medium known as ½ SME ''Ignicoccus''  which is a solution of synthetic sea water which is then made anaerobic.


Grown in this media at their optimal growth temperature of 90C, the members of the ''Ignicoccus''  genus typically reach a cell density of ~4x107cells/mL[[#References|[1]]] .


The addition of [http://en.wikipedia.org/wiki/Yeast_extract yeast extract] to the ½ SME media has been shown to stimulate the growth and increase maximum cell density achieved. The mechanism by which this is achieved is not known[[#References|[1]]] .


=References=


=Symbiosis=
(1)Begic, S., & Worobec, E. (2009). Characterization of the serratia marcescens SdeCDE multidrug efflux pump studied via gene knockout mutagenesis (vol 54, pg 411, 2008).Canadian Journal of Microbiology, 55(9), 1130-1131. doi:10.1139/W09-901
 
''Ignicoccus hospitalis''  is the only member of the genus ''Ignicoccus'' that has been shown to have an extensive [http://en.wikipedia.org/wiki/Symbiosis symbiotic relationship] with another organism.
 
''Ignicoccus hospitalis''  has been shown to engage in symbiosis with ''Nanoarchaeum equitans'' . ''Nanoarchaeum equitans''  is a very small coccoid species with a cell diameter of 0.4 µm[[#References|[9]]] . Genome analysis has provided much of the known information about this species.
 
To further complicate the symbiotic relationship between both species, it’s been observed that the presence of ''Nanoarchaeum equitans''  on the surface of ''Ignicoccus hospitalis''  somehow inhibits the cell replication of ''Ignicoccus hospitalis'' . How or why this occurs has not yet been elucidated[[#References|[3]]] .
 
[[File:Urzwerg.jpg|300px|thumb|right| ''Ignicoccus hospitalis'' with two attached  ''Nanoarchaeum equitans'' cells.]]
 
[[File:IhNeRelationship2 jpeg.jpg|250px|thumb|left| Epifluoroscence micrographs of an ''Ignicoccus hospitalis''and ''Nanoarchaeum equitans'' coculture stained with BacLight at various time points. Living cells stain green while dead cells stain red. (A) Exponential growth phase 3.25 hours after inoculation. (B) Transition into the stationary phase 7.5 hours after inoculation. (C) Stationary phase 10 hours after inoculation. (D) Stationary phase 23 hours after inoculation.]]
 
 
==''Nanoarchaeum equitans''==
 
''Nanoarchaeum equitans'' has the smallest non-viral genome ever sequenced at 491kb[[#References|[9]]] . Analysis of the genome sequence indicates that 95% of the predicted proteins and stable RNA molecules are somehow involved in repair and replication of the cell and its genome[[#References|[3]]] .
 
Analysis of the genome also showed that ''Nanoarchaeum equitans''  lacks nearly all genes known to be required in amino acid, nucleotide, cofactor and lipid metabolism. This is partially supported by the evidence that ''Nanoarchaeum equitans''  has been shown to derive its cell membrane from its host ''Ignicoccus hospitalis''  cell membrane. The direct contact observed between ''Nanoarchaeum equitans'' and ''Ignicoccus hospitalis''  is hypothesized to form a pore between the two organisms in order to exchange metabolites or substrates (likely from ''Ignicoccus hospitalis''  towards ''Nanoarchaeum equitans'' due to the parasitic relationship). The exchange of periplasmic vesicles is not thought to be involved in metabolite or substrate exchange despite the presence of vesicles in the periplasm of ''Ignicoccus hospitalis'' .


These analyses of the ''Nanoarchaeum equitans'' genome support the fact of the extensive symbiotic relationship between ''Nanoarchaeum equitans'' and ''Ignicoccus hospitalis''. However, it has not yet been proven that it is a strictly parasitic relationship and further research may prove that there is a commensal relationship between the two species.  
(2)Mahamoud, A., Chevalier, J., Alibert-Franco, S., Kern, W. V., & Pagès, J. (2007). Antibiotic efflux pumps in gram-negative bacteria: The inhibitor response strategy. Journal of Antimicrobial Chemotherapy, 59(6), 1223-1229. doi:10.1093/jac/dkl493
 
=References=


(1) Burggraf S., Huber H., Mayer T., Rachel R., Stetter K.O. and Wyschkony I. ” Ignicoccus gen. nov., a novel genus of hyperthermophilic, chemolithoautotrophic Archaea, represented by two new species, Ignicoccus islandicus sp. nov. and Ignicoccus pacificus sp. nov.” International Journal of Systematic and Evolutionary Microbiology, 2000, Volume 50.
(3) Chen, J., Lee, E., Kuroda, T., Mizushima, T., & Tsuchiya, T. (2003). Multidrug resistance in serratia marcescens and cloning of genes responsible for the resistance. Biological and Pharmaceutical Bulletin, 26(3), 391-393. doi:10.1248/bpb.26.391


(2) Naether D.J. and Rachel R. “The outer membrane of the hyperthermophilic archaeon Ignicoccus: dynamics, ultrastructure and composition.” Biochemical Society Transactions, 2004, Volume 32, part 2.
(4) Chen, J., Kuroda, T., Huda, M. N., Mizushima, T., & Tsuchiya, T. (2003). An RND-type multidrug efflux pump SdeXY from serratia marcescens. The Journal of Antimicrobial Chemotherapy, 52(2), 176-179. doi:10.1093/jac/dkg308


(3) Giannone R.J., Heimerl T., Hettich R.L., Huber H., Karpinets T., Keller M., Kueper U., Podar M. and Rachel R. “Proteomic Characterization of Cellular and Molecular Processes that Enable the Nanoarchaeum equitans- Ignicoccus hospitalis Relationship.” PLoS ONE, 2011, Volume 6, Issue 8.
(5) HEJAZI, A., & FALKINER, F. R. (1997). Serratia marcescens.Journal of Medical Microbiology, 46(11), 903-912. doi:10.1099/00222615-46-11-903


(4) Eisenreich W., Gallenberger M., Huber H., Jahn U., Junglas B., Paper W., Rachel R. and Stetter K.O. “Nanoarchaeum equitans and Ignicoccus hospitalis: New Insights into a Unique, Intimate Association of Two Archaea.” Journal of Bacteriology, 2008, DOI: 10.1128/JB.01731-07.
(6)Kumar, A., & Worobec, E. A.Cloning, sequencing, and characterization of the SdeAB multidrug efflux pump of serratia marcescens American Society for Microbiology.


(5) Grosjean E., Huber H., Jahn U., Sturt H, and Summons R. “Composition of the lipids of Nanoarchaeum equitans and their origin from its host Ignicoccus sp. strain KIN4/I.” Arch Microbiol, 2004, DOI: 10.1007/s00203-004-0725-x.
(7) Maseda, H., Hashida, Y., Shirai, A., Omasa, T., & Nakae, T. (2011). Mutation in the sdeS gene promotes expression of the sdeAB efflux pump genes and multidrug resistance in serratia marcescens. Antimicrobial Agents and Chemotherapy, 55(6), 2922-2926. doi:10.1128/AAC.01755-10


(6) Briegel A., Burghardt T., Huber H., Junglas B., Rachel R., Walther P. and Wirth R. “Ignicoccus hospitalis and Nanoarchaeum equitans: ultrastructure, cell–cell interaction, and 3D reconstruction from serial sections of freeze-substituted cells and by electron cryotomography.”  Arch Microbiol, 2008, DOI 10.1007/s00203-008-0402-6.
(8) Matsuo, T., Chen, J., Minato, Y., Ogawa, W., Mizushima, T., Kuroda, T., & Tsuchiya, T. (2008). SmdAB, a heterodimeric ABC-type multidrug efflux pump, in serratia marcescens.Journal of Bacteriology, 190(2), 648-654. doi:10.1128/JB.01513-07


(7) Burghardt T., Huber H., Junglas B., Naether D.J. and Rachel R. “The dominating outer membrane protein of the hyperthermophilic Archaeum Ignicoccus hospitalis: a novel pore-forming complex.” Molecular Microbiology, 2007, Volume 63.
(9) Minato, Y., Shahcheraghi, F., Ogawa, W., Kuroda, T., & Tsuchiya, T. (2008). Functional gene cloning and characterization of the SsmE multidrug efflux pump from serratia marcescens. Biological & Pharmaceutical Bulletin,31(3), 516-519. doi:10.1248/bpb.31.516


(8) Berg I.A., Eisenreich W., Eylert E., Fuchs G., Gallenberger M., Huber H.,Jahn U. and Kockelkorn D. “A dicarboxylate/4-hydroxybutyrate autotrophic carbon assimilation cycle in the hyperthermophilic Archaeum Ignicoccus hospitalis.” PNAS, 2008, Volume 105, issue 22.
(10) Shahcheraghi, F., Minato, Y., Chen, J., Mizushima, T., Ogawa, W., Kuroda, T., & Tsuchiya, T. (2007). Molecular cloning and characterization of a multidrug efflux pump, SmfY, from serratia marcescens. Biological & Pharmaceutical Bulletin, 30(4), 798-800.


(9) Brochier C., Gribaldo S.,  Zivanovic Y.,  Confalonieri F. and Forterre P. “Nanoarchaea: representatives of a novel archaeal phylum or a fast-evolving euryarchaeal lineage related to Thermococcales?” Genome Biology 2005, DOI:10.1186/gb-2005-6-5-r42.
(11) Sleigh, J. D. (1983). Antibiotic resistance in serratia marcescens. UK PubMed Central,


(10) Huber H., Rachel R., Riehl S. and Wyschkony I. “The ultrastructure of Ignicoccus: Evidence for a novel outer membrane and for intracellular vesicle budding in an archaeon.” Archaea, 2002, Volume 1.
(12) Webber, M. A., & Piddock, L. J. V. (2003). The importance of efflux pumps in bacterial antibiotic resistance. The Journal of Antimicrobial Chemotherapy, 51(1), 9-11. doi:10.1093/jac/dkg050

Latest revision as of 23:35, 26 November 2013

This student page has not been curated.

Introduction

Serratia marcescens is a gram-negative bacillus bacterium classified as a member of the Enterobacteriaceae family. It is an opportunistic pathogen and has been the cause of nosocomial infections for the past two decades[5]. S. marcescens is motile and a facultative anaerobe and is well known for its pink pigmented colonies which are commonly seen on the walls of bathtubs or tiles where soap residue is usually found. Many infections caused by S. marcescens are difficult to treat due to antibiotic resistance that the bacterium has developed[11]. Studies have shown that S. marcescens have multidrug resistance due to the efflux pumps that it maintains[3].

Serratia marcescens. Retrieved from http://commons.wikimedia.org/wiki/File:Serratia_marcescens.jpg

Efflux Pumps

Efflux pumps in bacterial cells are transport proteins that contribute to the expulsion of toxic substrates from inside the cell to the environment[12]. Such toxic substrates such as erythromycin, streptomycin and norflaxin, are clinically developed antibiotics that target the cell’s physiological processes. There are five major efflux pumps found in bacterial cells: MF (major facilitator), MATE (multidrug and toxic efflux), RND (resistance-nodulation-division), SMR (small multidrug resistance) and ABC (ATP-binding cassette)[12]. S. marcescens is found to have four of the five major efflux pumps. S. marcescens has been characterized to express three RND-type7 and one from the MF, SMR and ABC-type efflux pumps. Efflux pumps play an important role in the drug resistance capabilities of bacteria including Escherichia coli, especially in S. marcescens.

Figure 2. Different know bacterial efflux pumps in gram-negative bacteria. Shown in the diagram are the flow of substrates (drugs) and energy source for the different efflux pumps.


Serratia marcescens' Efflux Pumps

There are six efflux pumps found in S. marcescens that have been characterized:

SdeAB (Serratia’s drug efflux)

It is an RND-type (resistance-nodulation-cell division) efflux pump with genes that code for both an MF and RND-type efflux pumps. It uses a proton gradient as an energy source and consists of a tripartite complex protein. It mostly pumps out fluoroquinolones and is known to be the major fluoroquinolone pump in S. marcescens.[6],[7]

SdeCDE

It is an RND-type efflux pumps that is a combination of one MFP (membrane fusion protein for sdeC) and two RND (sdeDE) pump transporters which uses the proton gradient for energy. This type of efflux pump also exhibits a tripartite complex and is found to have restrictive selectivity only to novobiocin1. It is also found to be the third RND-type pump to be characterized for S. marcescens.[1]

SdeXY

It is an RND-type efflux pump which uses a proton gradient as an energy source. It is composed of two components to make up the complex: SdeX, a hydrophilic protein found to be an MFP; SdeY, an integral protein that has many hydrophobic residues and many transmembrane domains. It is resistant to a wide variety of antimicrobial agents and was the first RND-type to be characterized in S. marcescens[4].

SsmE (Serratia’s small multidrug resistance)

It is an SMR-type (small multidrug resistance) efflux pumps that is energy-dependent and works as a substrate/H+ antiporter and expels substrates out of the cell. It is composed of four transmembrane domains that span the cell membrane. It is particularly resistant to ethidium bromide and acriflavine and is known to be an ethidium efflux[9].

SmfY (Serratia’s major facilitator)

It is a member of the MF (major facilitator) superfamily transporters that is an energy-dependent efflux pump that contains numerous hydrophobic residues. These residues are long enough to extend around the cell membrane. It is commonly resistant to a known antiseptic called benzalkonium chloride. This is the very first MF-type multidrug efflux pump to be discovered[10].

SmdAB (for Serratia MultiDrug resistance)

It is an ABC-type (ATP-binding cassette) multidrug efflux pumps which utilizes ATP as an energy source. It is the very first report of a heterodimer that is seen working in a gram-negative bacterium. It is composed of six transmembrane segments and has hydrophilic segments which contain recognized-binding domains. It is found to be resistant to many cytotoxic agents like norflaxin or tetracycline. This was the very first ABC-type multidrug efflux pump to be characterized in S. marcescens[8].


Impact of Multidrug Resistant Efflux Pumps

The number of patients in recent years has greatly increased due to the drug resistance of S. marcescens[3]. Life threatening infections such as septicemia, endocarditis and meningitis are only some of the infections caused by S. marcescens[11]. Due to the evolutionary adaptations of S. marcescens in drug resistance, such infections stated are extremely difficult to treat. With the characterization and the further studies of the different multidrug efflux pumps, we are able to understand the mechanisms and the distinct antibiotics that S. marcescens is resistant to which is key in developing inhibitors and other mechanisms to hinder their function[11].

Figure 3. S. marcescens known to be pretty “bad-ass” towards multiple antibiotics. It regulates its genes to express more efflux pumps due to an increase in antibiotics in the environment.


Treatment

S. marcescens has increased stress in society due to its emerging resistance mechanisms that make its efflux pumps resistant to various antibiotics. Various mechanisms are formulated like controlling the membrane permeability or the production of innovative molecules which are insensitive to these resistant mechanisms for effective treatment[2]. Recent studies have formulated different strategies in order to elude the drug resistance efflux pumps by doing the following: generating better molecular designs to bypass the efflux activity, directly decreasing the effectiveness of the cell membrane with a channel blocker to induce “traffic jams”, and by blocking the efflux capacity by altering the function of the efflux pump in the bacterial cell wall with inhibition mechanisms[2].



References

(1)Begic, S., & Worobec, E. (2009). Characterization of the serratia marcescens SdeCDE multidrug efflux pump studied via gene knockout mutagenesis (vol 54, pg 411, 2008).Canadian Journal of Microbiology, 55(9), 1130-1131. doi:10.1139/W09-901

(2)Mahamoud, A., Chevalier, J., Alibert-Franco, S., Kern, W. V., & Pagès, J. (2007). Antibiotic efflux pumps in gram-negative bacteria: The inhibitor response strategy. Journal of Antimicrobial Chemotherapy, 59(6), 1223-1229. doi:10.1093/jac/dkl493

(3) Chen, J., Lee, E., Kuroda, T., Mizushima, T., & Tsuchiya, T. (2003). Multidrug resistance in serratia marcescens and cloning of genes responsible for the resistance. Biological and Pharmaceutical Bulletin, 26(3), 391-393. doi:10.1248/bpb.26.391

(4) Chen, J., Kuroda, T., Huda, M. N., Mizushima, T., & Tsuchiya, T. (2003). An RND-type multidrug efflux pump SdeXY from serratia marcescens. The Journal of Antimicrobial Chemotherapy, 52(2), 176-179. doi:10.1093/jac/dkg308

(5) HEJAZI, A., & FALKINER, F. R. (1997). Serratia marcescens.Journal of Medical Microbiology, 46(11), 903-912. doi:10.1099/00222615-46-11-903

(6)Kumar, A., & Worobec, E. A.Cloning, sequencing, and characterization of the SdeAB multidrug efflux pump of serratia marcescens American Society for Microbiology.

(7) Maseda, H., Hashida, Y., Shirai, A., Omasa, T., & Nakae, T. (2011). Mutation in the sdeS gene promotes expression of the sdeAB efflux pump genes and multidrug resistance in serratia marcescens. Antimicrobial Agents and Chemotherapy, 55(6), 2922-2926. doi:10.1128/AAC.01755-10

(8) Matsuo, T., Chen, J., Minato, Y., Ogawa, W., Mizushima, T., Kuroda, T., & Tsuchiya, T. (2008). SmdAB, a heterodimeric ABC-type multidrug efflux pump, in serratia marcescens.Journal of Bacteriology, 190(2), 648-654. doi:10.1128/JB.01513-07

(9) Minato, Y., Shahcheraghi, F., Ogawa, W., Kuroda, T., & Tsuchiya, T. (2008). Functional gene cloning and characterization of the SsmE multidrug efflux pump from serratia marcescens. Biological & Pharmaceutical Bulletin,31(3), 516-519. doi:10.1248/bpb.31.516

(10) Shahcheraghi, F., Minato, Y., Chen, J., Mizushima, T., Ogawa, W., Kuroda, T., & Tsuchiya, T. (2007). Molecular cloning and characterization of a multidrug efflux pump, SmfY, from serratia marcescens. Biological & Pharmaceutical Bulletin, 30(4), 798-800.

(11) Sleigh, J. D. (1983). Antibiotic resistance in serratia marcescens. UK PubMed Central,

(12) Webber, M. A., & Piddock, L. J. V. (2003). The importance of efflux pumps in bacterial antibiotic resistance. The Journal of Antimicrobial Chemotherapy, 51(1), 9-11. doi:10.1093/jac/dkg050

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