Editing Staphylococcus aureus (section)

=== Antibiotic resistance ===
{{Main|Antimicrobial resistance}}
[[Image:Staphylococcus aureus, 50,000x, USDA, ARS, EMU.jpg|thumb|right|250px|Bacterial cells of ''S. aureus'', which is one of the causal agents of [[Mastitis in dairy cattle|mastitis in dairy cows]]: Its large capsule protects the organism from attack by the cow's immunological defenses.]]
''Staphylococcus aureus'' was found to be the second leading pathogen for deaths associated with antimicrobial resistance in 2019.<ref>{{cite journal | vauthors = Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Aguilar GR, Gray A, etal | collaboration = Antimicrobial Resistance Collaborators | title = Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis | language = English | journal = Lancet | volume = 399 | issue = 10325 | pages = 629–655 | date = February 2022 | pmid = 35065702 | pmc = 8841637 | doi = 10.1016/S0140-6736(21)02724-0 }}</ref> <ref>{{cite journal | vauthors = Korotetskiy IS, Shilov SV, Kuznetsova TV, Zubenko N, Ivanova L, Reva ON | title = Epigenetic background of lineage-specific gene expression landscapes of four Staphylococcus aureus hospital isolates. | language = English | journal = PLOS ONE | volume = 20 | issue = 5 | pages = e0322006 | date = 2025 | pmid = 40323905 | pmc = 12052166 | doi = 10.1371/journal.pone.0322006 | doi-access = free | bibcode = 2025PLoSO..2022006K }}</ref>

Staphylococcal resistance to penicillin is mediated by [[Beta-lactamase#Penicillinase|penicillinase]] (a form of [[beta-lactamase]]) production: an enzyme that cleaves the [[β-lactam]] ring of the penicillin molecule, rendering the antibiotic ineffective. Penicillinase-resistant β-lactam antibiotics, such as [[methicillin]], [[nafcillin]], [[oxacillin]], [[cloxacillin]], [[dicloxacillin]], and [[flucloxacillin]] are able to resist degradation by staphylococcal penicillinase.{{citation needed|date=December 2022}}
[[File:Staphylococcus aureus susceptibility.jpg|thumb|Susceptibility to commonly used antibiotics.]]
Resistance to methicillin is mediated via the ''mec'' [[operon]], part of the staphylococcal cassette chromosome mec (SCC''mec''). SCCmec is a family of mobile genetic elements, which is a major driving force of ''S. aureus'' evolution.<ref name="Deurenberg_2008" /> Resistance is conferred by the ''mecA'' gene, which codes for an altered [[penicillin-binding protein]] (PBP2a or PBP2') that has a lower affinity for binding β-lactams (penicillins, [[cephalosporin]]s, and [[carbapenem]]s). This allows for resistance to all β-lactam antibiotics, and obviates their clinical use during MRSA infections. Studies have explained that this mobile genetic element has been acquired by different lineages in separate gene transfer events, indicating that there is not a common ancestor of differing MRSA strains.<ref>{{cite journal | vauthors = Jamrozy D, Coll F, Mather AE, Harris SR, Harrison EM, MacGowan A, Karas A, Elston T, Estée Török M, Parkhill J, Peacock SJ | title = Evolution of mobile genetic element composition in an epidemic methicillin-resistant ''Staphylococcus aureus'': temporal changes correlated with frequent loss and gain events | journal = BMC Genomics | volume = 18 | issue = 1 | pages = 684 | date = September 2017 | pmid = 28870171 | pmc = 5584012 | doi = 10.1186/s12864-017-4065-z | doi-access = free }}</ref> One study suggests that MRSA sacrifices virulence, for example, toxin production and invasiveness, for survival and creation of biofilms<ref>{{cite journal | vauthors = Pozzi C, Waters EM, Rudkin JK, Schaeffer CR, Lohan AJ, Tong P, Loftus BJ, Pier GB, Fey PD, Massey RC, O'Gara JP | title = Methicillin resistance alters the biofilm phenotype and attenuates virulence in ''Staphylococcus aureus'' device-associated infections | journal = PLOS Pathogens | volume = 8 | issue = 4 | pages = e1002626 | date = 2012-04-05 | pmid = 22496652 | pmc = 3320603 | doi = 10.1371/journal.ppat.1002626 | veditors = Sullam PM | doi-access = free }}</ref>

[[Aminoglycoside]] antibiotics, such as [[kanamycin]], [[gentamicin]], [[streptomycin]], were once effective against staphylococcal infections until strains evolved mechanisms to inhibit the aminoglycosides' action, which occurs via protonated amine and/or hydroxyl interactions with the [[ribosomal RNA]] of the bacterial [[30S ribosomal subunit]].<ref>{{cite journal | vauthors = Carter AP, Clemons WM, Brodersen DE, Morgan-Warren RJ, Wimberly BT, Ramakrishnan V | title = Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics | journal = Nature | volume = 407 | issue = 6802 | pages = 340–8 | date = September 2000 | pmid = 11014183 | doi = 10.1038/35030019 | s2cid = 4408938 | bibcode = 2000Natur.407..340C | url = https://resolver.caltech.edu/CaltechAUTHORS:20181030-134119194 }}</ref> Three main mechanisms of aminoglycoside resistance mechanisms are currently and widely accepted: aminoglycoside modifying enzymes, ribosomal mutations, and active [[efflux (microbiology)|efflux]] of the drug out of the bacteria.{{citation needed|date=August 2022}}

Aminoglycoside-modifying enzymes inactivate the aminoglycoside by covalently attaching either a [[phosphate]], [[nucleotide]], or [[acetyl]] moiety to either the amine or the alcohol key functional group (or both groups) of the antibiotic.  This changes the charge or sterically hinders the antibiotic, decreasing its ribosomal binding affinity.  In ''S. aureus'', the best-characterized aminoglycoside-modifying enzyme is aminoglycoside adenylyltransferase 4' IA (''ANT(4')IA''). This enzyme has been solved by [[X-ray crystallography]].<ref>{{cite journal | vauthors = Sakon J, Liao HH, Kanikula AM, Benning MM, Rayment I, Holden HM | title = Molecular structure of kanamycin nucleotidyltransferase determined to 3.0-A resolution | journal = Biochemistry | volume = 32 | issue = 45 | pages = 11977–84 | date = November 1993 | pmid = 8218273 | doi = 10.1021/bi00096a006 }}</ref> The enzyme is able to attach an [[adenine|adenyl]] moiety to the 4' hydroxyl group of many aminoglycosides, including [[kanamycin]] and gentamicin.{{citation needed|date=August 2022}}

Glycopeptide resistance is typically mediated by acquisition of the ''vanA'' gene, which originates from the Tn1546 transposon found in a plasmid in [[Enterococcus|enterococci]] and codes for an enzyme that produces an alternative [[peptidoglycan]] to which vancomycin will not bind.<ref>{{cite journal | vauthors = Arthur M, Courvalin P | title = Genetics and mechanisms of glycopeptide resistance in enterococci | journal = Antimicrobial Agents and Chemotherapy | volume = 37 | issue = 8 | pages = 1563–71 | date = August 1993 | pmid = 8215264 | pmc = 188020 | doi = 10.1128/AAC.37.8.1563 | publisher = ASM }}</ref>

Today, ''S. aureus'' has become [[antibiotic resistance|resistant]] to many commonly used antibiotics. In the UK, only 2% of all ''S. aureus'' isolates are sensitive to penicillin, with a similar picture in the rest of the world. The β-lactamase-resistant penicillins (methicillin, oxacillin, cloxacillin, and flucloxacillin) were developed to treat penicillin-resistant ''S. aureus'', and are still used as first-line treatment. Methicillin was the first antibiotic in this class to be used (it was introduced in 1959), but only two years later, the first case of methicillin-resistant ''Staphylococcus aureus'' (MRSA) was reported in England.<ref name="BMJ1961-Jevons">{{cite journal | vauthors = Rolinson GN, Stevens S, Batchelor FR, Wood JC, Chain EB | title = Bacteriological studies on a new penicillin-BRL. 1241 | journal = Lancet | volume = 2 | issue = 7150 | pages = 564–7 | date = September 1960 | pmc = 1952878 | doi = 10.1136/bmj.1.5219.124-a | pmid = 14438510 }}</ref>

Despite this, MRSA generally remained an uncommon finding, even in hospital settings, until the 1990s, when the MRSA prevalence in hospitals exploded, and it is now [[Endemic (epidemiology)|endemic]].<ref name="JAntimicrobChemother2001-Johnson">{{cite journal | vauthors = Johnson AP, Aucken HM, Cavendish S, Ganner M, Wale MC, Warner M, Livermore DM, Cookson BD | title = Dominance of EMRSA-15 and -16 among MRSA causing nosocomial bacteraemia in the UK: analysis of isolates from the European Antimicrobial Resistance Surveillance System (EARSS) | journal = The Journal of Antimicrobial Chemotherapy | volume = 48 | issue = 1 | pages = 143–4 | date = July 2001 | pmid = 11418528 | doi = 10.1093/jac/48.1.143 | doi-access = free }}</ref> Now, methicillin-resistant ''Staphylococcus aureus'' (MRSA) is not only a human pathogen causing a variety of infections, such as skin and soft tissue infection (SSTI), pneumonia, and sepsis, but it also can cause disease in animals, known as livestock-associated MRSA (LA-MRSA).<ref>{{cite journal | vauthors = Chen CJ, Huang YC | title = Emergence of livestock-associated methicillin-resistant ''Staphylococcus aureus'': Should it be a concern? | journal = Journal of the Formosan Medical Association = Taiwan Yi Zhi | volume = 117 | issue = 8 | pages = 658–661 | date = August 2018 | pmid = 29754805 | doi = 10.1016/j.jfma.2018.04.004 | s2cid = 21659477 | doi-access = free }}</ref>

MRSA infections in both the hospital and community setting are commonly treated with non-β-lactam antibiotics, such as [[clindamycin]] (a lincosamine) and co-trimoxazole (also commonly known as [[trimethoprim]]/[[sulfamethoxazole]]). Resistance to these antibiotics has also led to the use of new, broad-spectrum anti-Gram-positive antibiotics, such as [[linezolid]], because of its availability as an oral drug. First-line treatment for serious invasive infections due to MRSA is currently [[glycopeptide]] antibiotics (vancomycin and [[teicoplanin]]). A number of problems with these antibiotics occur, such as the need for intravenous administration (no oral preparation is available), toxicity, and the need to monitor drug levels regularly by blood tests. Also, glycopeptide antibiotics do not penetrate very well into infected tissues (this is a particular concern with infections of the brain and [[meninges]] and in [[endocarditis]]). Glycopeptides must not be used to treat methicillin-sensitive ''S. aureus'' (MSSA), as outcomes are inferior.<ref name="ArchInternMed2002-Blot">{{verify source|date=October 2011}}{{cite journal | vauthors = Blot SI, Vandewoude KH, Hoste EA, Colardyn FA | title = Outcome and attributable mortality in critically Ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant ''Staphylococcus aureus'' | journal = Archives of Internal Medicine | volume = 162 | issue = 19 | pages = 2229–35 | date = October 2002 | pmid = 12390067 | doi = 10.1001/archinte.162.19.2229 | doi-access = free }}</ref>

[[Daptomycin]] is a cyclic lipopeptide antibiotic primarily used for treating Gram-positive bacterial infections, including those caused by Staphylococcus aureus. It was first approved in 2003 and is especially effective against resistant strains like [[Methicillin-resistant Staphylococcus aureus|methicillin-resistant Staphylococcus aureus (MRSA)]] and [[Vancomycin-resistant Staphylococcus aureus#:~:text=Vancomycin-resistant Staphylococcus aureus (VRSA,from one bacterium to another.|vancomycin-resistant Staphylococcus aureus (VRSA).]]

Daptomycin works in a unique way compared to other antibiotics. It including calcium-dependent membrane binding, disruption of membrane potentia and bacterial cell death.Daptomycin is FDA-approved for treating complicated skin and soft tissue infections  and bloodstream infections and right-sided infective endocarditis caused by S. aureus.<ref>{{Cite journal |last1=Pader |first1=Vera |last2=Hakim |first2=Sanika |last3=Painter |first3=Kimberley L. |last4=Wigneshweraraj |first4=Sivaramesh |last5=Clarke |first5=Thomas B. |last6=Edwards |first6=Andrew M. |date=2016-10-24 |title=Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids |url=https://www.nature.com/articles/nmicrobiol2016194 |journal=Nature Microbiology |language=en |volume=2 |issue=1 |page=16194 |doi=10.1038/nmicrobiol.2016.194 |pmid=27775684 |issn=2058-5276|hdl=10044/1/40119 |hdl-access=free }}</ref>

Serum triggers a high degree of tolerance to the lipopeptide antibiotic daptomycin and several other classes of antibiotic.Serum-induced daptomycin tolerance is due to two independent mechanisms. The first one is the activation of the GraRS two-component system.<ref>{{Cite journal |last1=Yang |first1=Soo-Jin |last2=Bayer |first2=Arnold S. |last3=Mishra |first3=Nagendra N. |last4=Meehl |first4=Michael |last5=Ledala |first5=Nagender |last6=Yeaman |first6=Michael R. |last7=Xiong |first7=Yan Q. |last8=Cheung |first8=Ambrose L. |date=2012-12-22 |title=The Staphylococcus aureus Two-Component Regulatory System, GraRS, Senses and Confers Resistance to Selected Cationic Antimicrobial Peptides |journal=Infection and Immunity |volume=80 |issue=1 |pages=74–81 |doi=10.1128/iai.05669-11 |pmc=3255649 |pmid=21986630}}</ref> The activation is triggered by the host defense [[Cathelicidin antimicrobial peptide|LL-37]]. So that, bacteria can make more peptidoglycan to make the cell wall become thicker. This can make the tolerance of bacteria. The second one is the increase of cardiolipin abundance in the membrane.The serum-adapted bacteria can change their membrane composition. This change can reduce the binding of daptomycin to the bacteria’s membrane.<ref>{{Cite journal |last1=Ledger |first1=Elizabeth V. K. |last2=Mesnage |first2=Stéphane |last3=Edwards |first3=Andrew M. |date=2022-04-19 |title=Human serum triggers antibiotic tolerance in Staphylococcus aureus |journal=Nature Communications |language=en |volume=13 |issue=1 |pages=2041 |doi=10.1038/s41467-022-29717-3 |issn=2041-1723 |pmc=9018823 |pmid=35440121|bibcode=2022NatCo..13.2041L }}</ref>

Because of the high level of resistance to penicillins and because of the potential for MRSA to develop resistance to vancomycin, the [[U.S. Centers for Disease Control and Prevention]] has published guidelines<ref>{{Cite web |date=22 September 1995 |title=Recommendations for Preventing the Spread of Vancomycin Resistance Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC) |url=http://wonder.cdc.gov/wonder/prevguid/m0039349/m0039349.asp |url-status=dead |archive-url=https://web.archive.org/web/20060923012326/http://wonder.cdc.gov/wonder/prevguid/m0039349/m0039349.asp |archive-date=23 September 2006 |website=CDC}}</ref>  for the appropriate use of vancomycin. In situations where the incidence of MRSA infections is known to be high, the attending physician may choose to use a glycopeptide antibiotic until the identity of the infecting organism is known. After the infection is confirmed to be due to a methicillin-susceptible strain of ''S. aureus'', treatment can be changed to flucloxacillin or even penicillin, as appropriate.{{citation needed|date=December 2022}}

[[Vancomycin-resistant Staphylococcus aureus|Vancomycin-resistant ''S. aureus'']] (VRSA) is a strain of ''S. aureus'' that has become resistant to the glycopeptides. The first case of vancomycin-intermediate ''S. aureus'' (VISA) was reported in Japan in 1996;<ref name="JAntimicrobChemother1997-Hiramatsu">{{cite journal | vauthors = Hiramatsu K, Hanaki H, Ino T, Yabuta K, Oguri T, Tenover FC | title = Methicillin-resistant ''Staphylococcus aureus'' clinical strain with reduced vancomycin susceptibility | journal = The Journal of Antimicrobial Chemotherapy | volume = 40 | issue = 1 | pages = 135–6 | date = July 1997 | pmid = 9249217 | doi = 10.1093/jac/40.1.135 | doi-access = free }}</ref> but the first case of ''S. aureus'' truly resistant to glycopeptide antibiotics was only reported in 2002.<ref name="NEJM-Chang">{{cite journal | vauthors = Chang S, Sievert DM, Hageman JC, Boulton ML, Tenover FC, Downes FP, Shah S, Rudrik JT, Pupp GR, Brown WJ, Cardo D, Fridkin SK | title = Infection with vancomycin-resistant ''Staphylococcus aureus'' containing the vanA resistance gene | journal = The New England Journal of Medicine | volume = 348 | issue = 14 | pages = 1342–7 | date = April 2003 | pmid = 12672861 | doi = 10.1056/NEJMoa025025 | doi-access = free }}</ref> Three cases of VRSA infection had been reported in the United States as of 2005.<ref name="ClinMicroInf2005-Menichetti">{{cite journal | vauthors = Menichetti F | title = Current and emerging serious Gram-positive infections | journal = Clinical Microbiology and Infection | volume = 11 | issue = Suppl 3 | pages = 22–28 | date = May 2005 | pmid = 15811021 | doi = 10.1111/j.1469-0691.2005.01138.x | doi-access = free }}</ref> At least in part the antimicrobial resistance in ''S. aureus'' can be explained by its ability to adapt. Multiple two component signal transduction pathways helps ''S. aureus'' to express genes that are required to survive under antimicrobial stress.<ref name=":2">{{cite journal | vauthors = Sengupta M, Jain V, Wilkinson BJ, Jayaswal RK | title = Chromatin immunoprecipitation identifies genes under direct VraSR regulation in ''Staphylococcus aureus'' | journal = Canadian Journal of Microbiology | volume = 58 | issue = 6 | pages = 703–8 | date = June 2012 | pmid = 22571705 | doi = 10.1139/w2012-043 }}</ref>

==== Efflux pumps ====
Among the various mechanisms that MRSA acquires to elude antibiotic resistance (e.g., drug inactivation, target alteration, reduction of permeability) there is also the overexpression of [[efflux pump]]s. Efflux pumps are membrane-integrated proteins that are physiologically needed in the cell for the exportation of xenobiotic compounds. They are divided into six families, each of which has a different structure, function, and transport of energy. The main efflux pumps of ''S. aureus'' are the MFS ([[Major Facilitator Superfamily]]) which includes the MdeA pump as well as the NorA pump and the MATE (Multidrug and Toxin Extrusion) to which it belongs the MepA pump. For transport, these families use an electrochemical potential and an ion concentration gradient, while the ATP-binding cassette (ABC) family acquires its energy from the hydrolysis of ATP.{{citation needed|date=December 2022}}

These pumps are overexpressed by MDR ''S. aureus'' (Multidrug resistant ''S. aureus)'' and the result is an excessive expulsion of the antibiotic outside the cell, which makes its action ineffective. Efflux pumps also contribute significantly to the development of impenetrable biofilms.{{citation needed|date=December 2022}}

By directly modulating efflux pumps' activity or decreasing their expression, it may be possible to modify the resistant phenotype and restore the effectiveness of existing antibiotics.<ref>{{cite journal | vauthors = Holasová K, Křížkovská B, Hoang L, Dobiasová S, Lipov J, Macek T, Křen V, Valentová K, Ruml T, Viktorová J | title = Flavonolignans from silymarin modulate antibiotic resistance and virulence in ''Staphylococcus aureus'' | journal = Biomedicine & Pharmacotherapy | volume = 149 | pages = 112806 | date = May 2022 | pmid = 35303568 | doi = 10.1016/j.biopha.2022.112806 | doi-access = free }}</ref>