Lipid A phosphoethanolamine transferase (EC 2.7.8.43, lipid A PEA transferase, LptA, formerly EC 2.7.4.30) is an enzyme that modifies Lipid A by linkage to a phosphoethanolamine moiety. Doing so at some positions reduces the affinity to colistin and related polymyxins, resulting in reduced activity of the antimicrobial. This type of resistance is known as target modification.[1] This type of enzyme is of special medical note, as it offers resistance to a last-resort antibiotic.[2] The modifications also provide cross-resistance to host immunity factors, specifically antimicrobial peptides and lysozyme.[3][4] EC 2.7.8.43 catalyzes one of the following three reactions:[5]
a 1,2-diacyl-sn-glycero-3-phosphoethanolamine + H(+) + lipid A (E. coli) a 1,2-diacyl-sn-glycerol + lipid A hexaacyl 1-(2-aminoethyl diphosphate)
a 1,2-diacyl-sn-glycero-3-phosphoethanolamine + H(+) + lipid A (E. coli) a 1,2-diacyl-sn-glycerol + lipid A 4'-(2-aminoethyl diphosphate) (E. coli)
a 1,2-diacyl-sn-glycero-3-phosphoethanolamine + H(+) + lipid A hexaacyl 1-(2-aminoethyl diphosphate) a 1,2-diacyl-sn-glycerol + lipid A 1,4'-bis(2-aminoethyl diphosphate)
Enzyme databases may list a very long list of synonyms for this enzyme. Many of these names, such as mcr-1, do not refer to this type of enzyme in general, but only to a specific member of the family.[6] There are many non-mobile (chromosomal) versions of this enzyme scattered all around the evolutionary tree, but mcr-1 was notable because it was found on a plasmid, therefore capable of horizontal gene transfer.[7] Only one family of protein is currently known to perform the activity described by the EC number.
Structure
The enzyme is composed of two domains. The N-terminal part (about 1/3 of the length) is a transmembrane domain, while the rest is catalytic. Both domains contribute to the phosphoethanolamine substrate cavity. The C-terminal domain binds zinc as a cofactor.[7]
Function
Polymyxins and other cationic antimicrobial peptides attach to the LPS cell walls of bacteria by virtue of the highly negatively-charged groups in LPS such as Lipid A and Kdo. Modification of LPS with positively-charged PEA shields these sites from binding.[8]
Not all members of this family perform the same reaction, contrary to the EC classification framework. For example, E. coli naturally has three related genes all from this family, EptA through C, all with different preferences for where to attach PEA. Addition of PEA can happen on Lipid A (this EC entry), on Kdo (EC 2.7.8.42), or on Heptose 1 (no EC number), the latter two being parts of the core oligosaccharide. In the case of EptC, addition of PEA to Heptose compacts the LPS by forming a network of hydrogen bonds.[9]
Regulation
In chromosomal versions of this enzyme, the gene is regulated by a two-component regulatory system termed PmrAB or BasRS. The PmrA or BasS is the histidine kinase sensor, which activates the DNA-binding response regulatorBasR or PmrB. The sensor triggers in a variety of dangerous situations, such as metal ions and being ingested by a phagocyte, helping the bacterium build a stronger cell wall to survive. The PhoPQ system, which detects similar situations and the presence of antimicrobial peptides, can also cross-trigger PmrA via a PmrD connector. Antibiotic resistance can occur when this system, or its upstream signals, mutates to become constitutively active.[10]
In plasmid versions, the gene is simply constitutively activated by an upstream promoter.[10] The extra metabolic resources diverted means that the resistant trait is disadvantageous in environments without antibiotic or antimicrobial peptide threats, specifically by about 3%.[4]
Polymyxins are antibiotics. Polymyxins B and E are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial cell membrane. They are part of a broader class of molecules called nonribosomal peptides.
Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as colistin. Resistance to colistin began to appear as of 2015.
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UDP-4-amino-4-deoxy-L-arabinose formyltransferase is an enzyme with systematic name 10-formyltetrahydrofolate:UDP-4-amino-4-deoxy-beta-L-arabinose N-formyltransferase. This enzyme catalyses the following chemical reaction
Lipid IVA 4-amino-4-deoxy-L-arabinosyltransferase is an enzyme with systematic name 4-amino-4-deoxy-alpha-L-arabinopyranosyl ditrans, octacis-undecaprenyl phosphate:lipid IVA 4-amino-4-deoxy-L-arabinopyranosyltransferase. This enzyme catalyses the following chemical reaction
D-glycero-beta-D-manno-heptose 1-phosphate adenylyltransferase is an enzyme with systematic name ATP:D-glycero-beta-D-manno-heptose 1-phosphate adenylyltransferase. This enzyme catalyses the following chemical reaction
Undecaprenyl-phosphate 4-deoxy-4-formamido-L-arabinose transferase is an enzyme with systematic name UDP-4-amino-4-deoxy-alpha-L-arabinose:ditrans,octacis-undecaprenyl phosphate 4-amino-4-deoxy-alpha-L-arabinosyltransferase. This enzyme catalyses the following chemical reaction
Diacylglycerol diphosphate phosphatase (EC 3.1.3.81, DGPP phosphatase, DGPP phosphohydrolase, DPP1, DPPL1, DPPL2, PAP2, pyrophosphate phosphatase) is an enzyme with systematic name 1,2-diacyl-sn-glycerol 3-phosphate phosphohydrolase. This enzyme catalyses the following chemical reaction
The mobilized colistin resistance (mcr) gene confers plasmid-mediated resistance to colistin, one of a number of last-resort antibiotics for treating Gram-negative infections. mcr-1, the original variant, is capable of horizontal transfer between different strains of a bacterial species. After discovery in November 2015 in E. coli from a pig in China it has been found in Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. As of 2017, it has been detected in more than 30 countries on 5 continents in less than a year.
↑ Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J (February 2016). "Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study". The Lancet. Infectious Diseases. 16 (2): 161–8. doi:10.1016/S1473-3099(15)00424-7. PMID26603172.
↑ Anaya-López, José Luis; López-Meza, Joel Edmundo; Ochoa-Zarzosa, Alejandra (May 2013). "Bacterial resistance to cationic antimicrobial peptides". Critical Reviews in Microbiology. 39 (2): 180–195. doi:10.3109/1040841x.2012.699025. PMID22799636. S2CID35828720.
↑ Salazar, Javier; Alarcón, Mackarenna; Huerta, Jaime; Navarro, Belén; Aguayo, Daniel (April 2017). "Phosphoethanolamine addition to the Heptose I of the Lipopolysaccharide modifies the inner core structure and has an impact on the binding of Polymyxin B to the Escherichia coli outer membrane". Archives of Biochemistry and Biophysics. 620: 28–34. doi:10.1016/j.abb.2017.03.008. PMID28342805.
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