Editing Staphylococcus aureus (section)

=== Other immunoevasive strategies ===

;Protein A

[[Protein A]] is anchored to staphylococcal [[peptidoglycan]] pentaglycine bridges (chains of five [[glycine]] residues) by the [[Peptidyl transferase|transpeptidase]] [[sortase]] A.<ref>{{cite journal | vauthors = Schneewind O, Fowler A, Faull KF | title = Structure of the cell wall anchor of surface proteins in ''Staphylococcus aureus'' | journal = Science | volume = 268 | issue = 5207 | pages = 103–6 | date = April 1995 | pmid = 7701329 | doi = 10.1126/science.7701329 | bibcode = 1995Sci...268..103S }}</ref> Protein A, an [[Immunoglobulin G|IgG]]-binding protein, binds to the [[Fc region]] of an [[antibody]].  In fact, studies involving mutation of genes coding for protein A resulted in a lowered virulence of ''S. aureus'' as measured by survival in blood, which has led to speculation that protein A-contributed virulence requires binding of antibody Fc regions.<ref>{{cite journal | vauthors = Patel AH, Nowlan P, Weavers ED, Foster T | title = Virulence of protein A-deficient and alpha-toxin-deficient mutants of ''Staphylococcus aureus'' isolated by allele replacement | journal = Infection and Immunity | volume = 55 | issue = 12 | pages = 3103–10 | date = December 1987 | pmid = 3679545 | pmc = 260034 | doi = 10.1128/IAI.55.12.3103-3110.1987 }}</ref>

Protein A in various recombinant forms has been used for decades to bind and purify a wide range of antibodies by [[immunoaffinity chromatography]].  Transpeptidases, such as the sortases responsible for anchoring factors like protein A to the staphylococcal peptidoglycan, are being studied in hopes of developing new antibiotics to target MRSA infections.<ref>{{cite journal | vauthors = Zhu J, Lu C, Standland M, Lai E, Moreno GN, Umeda A, Jia X, Zhang Z | title = Single mutation on the surface of ''Staphylococcus aureus'' Sortase A can disrupt its dimerization | journal = Biochemistry | volume = 47 | issue = 6 | pages = 1667–74 | date = February 2008 | pmid = 18193895 | doi = 10.1021/bi7014597 }}</ref>

[[File:Staphylococcus aureus on TSA.jpg|thumb|''S. aureus'' on [[trypticase soy agar]]:  The strain is producing a yellow pigment [[staphyloxanthin]]. ]]

;Staphylococcal pigments

Some strains of ''S. aureus'' are capable of producing [[staphyloxanthin]] – a golden-coloured [[carotenoid]] [[pigment]].  This pigment acts as a [[virulence factor]], primarily by being a bacterial [[antioxidant]] which helps the microbe evade the [[reactive oxygen species]] which the host immune system uses to kill pathogens.<ref name="staphylotoxin">{{cite journal | vauthors = Clauditz A, Resch A, Wieland KP, Peschel A, Götz F | title = Staphyloxanthin plays a role in the fitness of ''Staphylococcus aureus'' and its ability to cope with oxidative stress | journal = Infection and Immunity | volume = 74 | issue = 8 | pages = 4950–3 | date = August 2006 | pmid = 16861688 | pmc = 1539600 | doi = 10.1128/IAI.00204-06 }}</ref><ref name="JExpMed2005-Liu">{{cite journal | vauthors = Liu GY, Essex A, Buchanan JT, Datta V, Hoffman HM, Bastian JF, Fierer J, Nizet V | title = ''Staphylococcus aureus'' golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity | journal = The Journal of Experimental Medicine | volume = 202 | issue = 2 | pages = 209–215 | date = July 2005 | pmid = 16009720 | pmc = 2213009 | doi = 10.1084/jem.20050846 }}</ref>

[[Mutant|Mutant strains]] of ''S. aureus'' modified to lack staphyloxanthin are less likely to survive incubation with an oxidizing chemical, such as [[hydrogen peroxide]], than pigmented strains. Mutant colonies are quickly killed when exposed to human [[Neutrophil granulocyte|neutrophils]], while many of the pigmented colonies survive.<ref name="staphylotoxin" /> In mice, the pigmented strains cause lingering [[abscess]]es when inoculated into wounds, whereas wounds infected with the unpigmented strains quickly heal.{{citation needed|date=December 2022}}

These tests suggest the ''Staphylococcus'' strains use staphyloxanthin as a defence against the normal human immune system.  Drugs designed to inhibit the production of staphyloxanthin may weaken the bacterium and renew its susceptibility to antibiotics.<ref name="JExpMed2005-Liu"/> In fact, because of similarities in the pathways for biosynthesis of staphyloxanthin and human [[cholesterol]], a drug developed in the context of cholesterol-lowering therapy was shown to block ''S. aureus'' pigmentation and disease progression in a [[mouse model|mouse infection model]].<ref name="Science2008-Liu">{{cite journal | vauthors = Liu CI, Liu GY, Song Y, Yin F, Hensler ME, Jeng WY, Nizet V, Wang AH, Oldfield E | title = A cholesterol biosynthesis inhibitor blocks ''Staphylococcus aureus'' virulence | journal = Science | volume = 319 | issue = 5868 | pages = 1391–4 | date = March 2008 | pmid = 18276850 | pmc = 2747771 | doi = 10.1126/science.1153018 | bibcode = 2008Sci...319.1391L }}</ref>

;Resistance to Hypothiocyanous Acid (HOSCN)

''Staphylococcus aureus'' has developed an adaptive mechanism to tolerate [[hypothiocyanous acid]] (HOSCN), a potent oxidant produced by the human immune system.<ref name="Barrett2012">{{cite journal |last1=Barrett |first1=T. J. |last2=Hawkins |first2=C. L. |year=2012 |title=Hypothiocyanous Acid: Benign or Deadly? |journal=Chemical Research in Toxicology |volume=25 |issue=2 |pages=263–273 |doi=10.1021/tx200219s|pmid=22053976 }}</ref><ref name="Loi2023">{{cite journal |last1=Loi |first1=V. Van |last2=Busche |first2=T. |last3=Schnaufer |first3=F. |last4=Kalinowski |first4=J. |last5=Antelmann |first5=H. |year=2023 |title=The neutrophil oxidant hypothiocyanous acid causes a thiol-specific stress response and an oxidative shift of the bacillithiol redox potential in ''Staphylococcus aureus'' |journal=Microbiology Spectrum |volume=11 |issue=6 |pages=e03252-23 |doi=10.1128/spectrum.03252-23|pmid=37930020 |pmc=10715087 }}</ref> Compared to other methicillin-resistant ''S. aureus'' ([[MRSA]]) strains and bacterial pathogens such as ''[[Pseudomonas aeruginosa]]'', ''Escherichia coli'', and ''[[Streptococcus pneumoniae]]'', ''S. aureus'' exhibits greater resistance to HOSCN.<ref name="Shearer2023">{{cite journal |last1=Shearer |first1=H. L. |last2=Loi |first2=V. V. |last3=Weiland |first3=P. |last4=Bange |first4=G. |last5=Altegoer |first5=F. |last6=Hampton |first6=M. B. |last7=Antelmann |first7=H. |last8=Dickerhof |first8=N. |year=2023 |title=MerA functions as a hypothiocyanous acid reductase and defense mechanism in ''Staphylococcus aureus'' |journal=Molecular Microbiology |volume=119 |issue=4 |pages=456–470 |doi=10.1111/MMI.15035|doi-access=free |pmid=36779383 }}</ref>  

This resistance is linked to the ''merA'' gene, which encodes a flavoprotein disulfide reductase (FDR) enzyme.<ref name="Shearer2023"/> ''S. aureus'' MerA shares similarities with HOSCN reductases from other bacteria, including ''S. pneumoniae'' (50% [[sequence identity]], 66% positives) and RclA in ''[[E. coli]]'' (50% sequence identity, 65% positives).<ref name="Shearer2023"/> These enzymes play a crucial role in [[oxidative stress]] defense by using [[NADPH]] as a [[Cofactor (biochemistry)|cofactor]] to reduce [[disulfide bonds]], thereby mitigating the [[oxidative damage]] caused by HOSCN.<ref name="Shearer2022">{{cite journal |last1=Shearer |first1=H. L. |last2=Pace |first2=P. E. |last3=Paton |first3=J. C. |last4=Hampton |first4=M. B. |last5=Dickerhof |first5=N. |year=2022 |title=A newly identified flavoprotein disulfide reductase Har protects ''Streptococcus pneumoniae'' against hypothiocyanous acid |journal=Journal of Biological Chemistry |volume=298 |issue=9 |pages=102359 |doi=10.1016/J.JBC.2022.102359|doi-access=free |pmid=35952759 |pmc=9483559 }}</ref> This mechanism enhances ''S. aureus'' survival within the host by counteracting the immune system’s oxidative attack.<ref name="Loi2023"/><ref name="Shearer2023"/>  

Functional characterization of MerA has revealed that the amino acid residue Cys43 (C43) is essential for its enzymatic activity against HOSCN.<ref name="Shearer2022"/> Additionally, the expression of ''merA'' in ''S. aureus'' is regulated by the ''hypR'' gene, a transcriptional suppressor that modulates the bacterial response to oxidative stress.<ref name="Shearer2023"/>