Antibiotic Resistance Genes in Staphylococcus spp.

Staphylococcus is a genus of Gram-positive, catalase-positive cocci bacteria in the family Staphylococcacceae of the order Bacillales. Despite being the most abundant normal flora of human skin and nasal cavity, Staphylococcus aureus, S. saprophyticus, and S. epidermidis are notorious opportunistic pathogens causing a wide range of infections like UTIs, RTIs, wound infections, BSIs, food-poisoning, etc.

Several antibiotics are used to treat such infections caused by Staphylococcus spp. However, the development of antibiotic resistance is no longer alienated from the Staph group. Several antibiotics that are preferred to treat the Staph infections such as Vancomycin, methicillin, cefoxitin, ciprofloxacin, ofloxacin, norfloxacin, azithromycin, streptomycin, erythromycin, etc. are now no longer effective in many of the clinical isolates.

Antibiotic Resistance Genes in Staphylococcus spp.
Antibiotic Resistance Genes in Staphylococcus spp.

Modification of target sites, over-expression of effluxes, synthesis of antibiotic modifying enzymes, etc. are common mechanisms developed by bacteria to resist antibiotics. Several genes are responsible for the development of such ABR mechanisms.

Some of the common antibiotic resistance genes (ARGs) found in Staphylococcus spp. are described in this note.

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mecA Gene

  • Methicillin-resistant determinant (mec) A gene is a bacterial gene that confers resistance to the bacteria against penicillin and penicillin-like antibiotics. It is an antibiotic-resistance gene found in Staphylococcus spp. that protects the bacteria against the bactericidal effect of methicillin and oxacillin and other penicillin family members. 
  • It is exclusively reported in Staphylococcus aureus, most commonly in Methicillin-Resistant Staphylococcus aureus (MRSA). Besides, mecA is reported in other Staphylococcus species like S. epidermidis, S. haemolyticus, S. sciuri, S. fleurettii, etc. 
  • The most important and major cause for the emergence of MRSA is the presence of the mecA gene. In most MRSA strains, the mecA gene is present in a 21- to 60-kbp long mobile genetic element (genomic island) called Staphylococcal Cassette Chromosome mec (SCCmec). From this SCCmec the mecA genes spread in the Staphylococcus genus via the horizontal gene transfer method and cause the rapid emergence of penicillin-resistant Staphylococcus spp.

Mechanism of Conferring Resistance of mecA gene

  • mecA gene is mainly noted for its ability to make Staphylococcus resistant to penicillin antibiotics mainly methicillin. These antibiotics are β- lactam antibiotics and act by binding with the bacterial transpeptidases, commonly called Penicillin Binding Proteins (PBPs), and prohibiting the complete formation of the bacteria cell wall.
  • mecA gene codes for the formation of alternative PBPs called PBP2a. β- lactam antibiotics have a lower affinity towards PBP2a. They lack the receptors for such antibiotics so β- lactam antibiotics can’t bind with them and prevent them from their transpeptidation process. Hence, antibiotics can’t disrupt the process of bacterial cell wall formation and allow bacteria to keep their cellular integrity. And ultimately, there is no effect of methicillin, oxacillin, and other similar penicillins on the bacteria with the mecA gene.     

Detection Method of mecA gene

  • mecA gene can be identified by using molecular techniques like PCR, DNA microarray method, probe detection method, etc. The phenotypic method like antimicrobial sensitivity testing of Staphylococcus spp. against methicillin, oxacillin, and cefoxitin are also used; however, they may show a false positive result. Hence, molecular detection is the only suitable method available.  
  • The most important and commonly used method is detection via Polymerase Chain Reaction (PCR) method. The primers that can be used for the detection of the mecA gene via PCR method are:
PRIMERSREFERENCES
F: 5′-AAA ATC GAT GGT AAA GGT TGG C-3′

R: 5′-AGT TCT GCA GTA CCG GAT TTG C-3′
Nam LV, Quyet D, Hung PN, et al.:
Antibiotic Resistance Profile and Methicillin-Resistant Encoding Genes of Staphylococcus aureus Strains Isolated from Bloodstream Infection Patients in Northern Vietnam. 
Open Access Maced J. Med. Sci. 2019; 7(24): 4406–4410.
F: 5′-GTT GTA GTT GTC GGG TTT GG-3′

R: 5′CTT CCA CAT ACC ATC TTC TTT AAC-3′
Wielders, L. C., Fluit, A. C., Brisse, S., Verhoef, J., & Schmitz, F. J. (2002).
mecA Gene Is Widely Disseminated in Staphylococcus aureus Population.
Journal of Clinical Microbiology, 40(11), 3970-3975. https://doi.org/10.1128/JCM.40.11.3970-3975.2002
F: 5′- GTA GAA ATG ACT GAA CGT CCG ATA A − 3′

R: 5′- CCA ATT CCA CAT TGT TTC GGT CTA A – 3′
Rao, S., Linke, L., Magnuson, R., Jauch, L., & Hyatt, D. R. (2022).
Antimicrobial resistance and genetic diversity of Staphylococcus aureus collected from livestock, poultry and humans.
One Health, 15. https://doi.org/10.1016/j.onehlt.2022.100407

VanA Gene

  • VanA gene is an antibiotic-resistant gene that confers resistance against vancomycin to bacterial strains containing it. It is mainly reported in Enterococcus spp., and Vancomycin-Resistant Enterococcus (VRE). Vancomycin-Resistant Staphylococcus aureus (VRSA) acquires this resistant gene from VRE
  • It is present in plasmid or transposons and from there it can be horizontally transferred to other Vancomycin sensitive strains of Enterococcus and Staphylococcus

Mechanism of Conferring Resistance of VanA Gene

  • VanA gene encodes for the synthesis of altered peptidoglycan precursors resulting in prohibition in the cross-linking process during the synthesis of the cell wall. This prevents bacteria from forming their cell wall and induces their death.  
  • In absence of the VanA gene, bacteria synthesize D-alanyl-D-alanine in N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) peptides. However, the VanA gene encodes for the production of D-alanyl-D-lactate and   D-alanyl-D-serine instead of D-alanyl-D-alanine. 
  • Vancomycin and teicoplanin bind to the two terminal D-ala residues and prevent from cross-linking. But, they can’t bind to the terminal D-lactate or D-serine residues. Hence, the antibiotics can’t prevent the cross-linking step, and bacteria can synthesize cell walls and maintain their cellular integrity.   

Detection Method of VanA Gene

  • Polymerase Chain Reaction (PCR) is the most important and widely used molecular detection method to identify the VanA gene in bacterial DNA. Commonly used primers for the detection of the VanA gene are:
Primers (Forward ‘F’ and Reverse ‘R’)References
F: 5´-TGAATAACATCGGCATTAC-3´

R: 5´-TTATTTAACGGGGAAATC-3´
Saha B, Singh AK, Ghosh A, Bal M. Identification and characterization of a vancomycin-resistant Staphylococcus aureus isolated from Kolkata (South Asia). J Med Microbiol. 2008;57;72-9. 

qac Gene

  • qac gene (quaternary ammonium compound gene) is an antibiotic-resistant gene that confers resistance against quaternary ammonium compounds (QACs) and cationic biocides (disinfectants like chlorhexidine, benzalkonium chloride, cetakolnium chloride, tetraethylammonium bromide, sodium chloride, etc) to bacterial strains containing it. It is reported in different strains of Staphylococcus bacteria worldwide. These genes are plasmid-encoded genes and are capable of transferring to another susceptible bacterium. 
  • Staphylococcus aureus and S. epidermidis are mostly known to contain this gene in them. Several clinical isolates of MRSA, MSSP, and VRSA are also reported to have the qac gene. There are 6 major members of the qac gene family; qacA and qacB are members of the Major Facilitator Superfamily and qacC, qacG, qacH, and qacJ are the members of the Minor Facilitator Superfamily. qacA, qacB, and qacC genes are mainly detected members of qac gene families in them. 
  • qacA and qacB genes are very similar; only 7 base pairs are different in their entire gene. Hence, they are commonly studied and detected together as qacA/B genes. They can be, however, differentiated by the fact that the qacA gene confers high resistance to both the monovalent cations (like ethidium, benzalkonium chloride, cetrimide, etc.) and divalent cations whereas, the qacB gene confers very low to no resistance against the divalent cations (like chlorhexidine and pentamidine).  

Mechanism of Conferring Resistance of qac Gene

  • qac genes encode for the formation of multidrug efflux pumps in the bacterial membranes. These efflux pumps are membrane proteins that export quaternary ammonium compounds out from the cytoplasm of the bacteria and confer resistance or higher tolerance against such disinfectants. These efflux pumps are energy-dependent efflux pumps depending on proton motive forces to expel QACs from the bacterial cytoplasm. 
  • Different qac genes encode for different types of qac efflux pumps. However, the roles and modes of action of all the pumps are almost the same. 

Detection Method of qac Gene

  • PCR remains the most important tool to detect the qac genes in Staphylococcus species. Commonly used primers for the detection of different types of qac genes are: 
qac gene typePrimersReferences
qacA geneF: 5´-CACCTACATCAAAAGCAGGTAATG-3´

R: 5´-CACGATAAAGCATAGAAGATAGGC -3´
Cervinkova, Dana; Babak, Vladimir; Marosevic, Durdica; Kubikova, Iva; Jaglic, Zoran (2013). The Role of the <i>qacA</i> Gene in Mediating Resistance to Quaternary Ammonium Compounds. Microbial Drug Resistance, 19(3), 160–167. doi:10.1089/mdr.2012.0154 
qacA/B genesF: 5´-CTATGGCAATAGGAGATATGGTGT-3´

R: 5´- CCACTACAGATTCTTCAGCTACATG-3´
Mayer, S. (2001). Distribution of the antiseptic resistance genes qacA, qacB, and qacC in 497 methicillin-resistant and -susceptible European isolates of Staphylococcus aureus. Journal of Antimicrobial Chemotherapy, 47(6), 896–897. doi:10.1093/jac/47.6.896 
qacA/B genes F: 5´-GCAGAAAGTGCAGAGTTCG-3´

R:5´-CCAGTCCAATCATGCCTG-3´
Noguchi N, Suwa J, Narui K, Sasatsu M, Ito T, Hiramatsu K, Song JH. Susceptibilities to antiseptic agents and distribution of antiseptic-resistance genes qacA/B and smr of methicillin-resistant Staphylococcus aureus isolated in Asia during 1998 and 1999. J Med Microbiol. 2005;54:557–565.
qacA/B genesF: 5´-GCTGCATTTATGACAATGTTTG-3´

R: 5´-AATCCCACCTACTAAAGCAG-3´
Vali L, Davies SE, Lai LLG, Dave J, Amyes SGB. Frequency of biocide resistance genes, antibiotic resistance and the effect of chlorhexidine exposure on clinical methicillin-resistant Staphylococcus aureus isolates. J Antimicrob Chemother. 2008;61(3):524–532
qacC geneF: 5´-AAACAATGCAACACCTACCACT-3´

R: 5´-AACGAAACTACGCCGACTATG-3´
Mayer, S. (2001). Distribution of the antiseptic resistance genes qacA, qacB and qacC in 497 methicillin-resistant and -susceptible European isolates of Staphylococcus aureus. Journal of Antimicrobial Chemotherapy, 47(6), 896–897. doi:10.1093/jac/47.6.896 
qacC geneF: 5´-ATAAGTACTGAAGTTATTGGAAGT-3´

R: 5´-TTCCGAAAATGTTTAACGAAACTA-3´
Vali L, Davies SE, Lai LLG, Dave J, Amyes SGB. Frequency of biocide resistance genes, antibiotic resistance and the effect of chlorhexidine exposure on clinical methicillin-resistant Staphylococcus aureus isolates. J Antimicrob Chemother. 2008;61(3):524–532
qacG geneF: 5´-TTTCGTTTGGAATTTGCTTT-3´

R: 5´-AATGGCTTTCTCCAAATACA-3´
Smith K, Gemmell CG, Hunter IS. The association between biocide tolerance and the presence or absence of qac genes among hospital-acquired and community-acquired MRSA isolates. J Antimicrob Chemother. 2008;61:78–84.
qacG geneF: 5´-CAACAGAAATAATCGGAACT-3´

R: 5´-TACATTTAAGAGCACTACA-3´
Bjorland J, Steinum T, Kvitle B, Waage S, Sunde M, Heir E. Widespread distribution of disinfectant resistance genes among Staphylococci of bovine and caprine origin in Norway. J Clin Microbiol. 2005;43:4363–4368.
qacH geneF: 5´-ATAGTCAGTGAAGTAATAG-3´

R: 5´-AGTGTGATGATCCGAATGT-3´
Bjorland J, Steinum T, Kvitle B, Waage S, Sunde M, Heir E. Widespread distribution of disinfectant resistance genes among Staphylococci of bovine and caprine origin in Norway. J Clin Microbiol. 2005;43:4363–4368.
qacJ geneF: 5´-CTTATATTTAGTAATAGCG-3´

R: 5´-GATCCAAAAACGTTAAGA-3´
Bjorland J, Steinum T, Kvitle B, Waage S, Sunde M, Heir E. Widespread distribution of disinfectant resistance genes among Staphylococci of bovine and caprine origin in Norway. J Clin Microbiol. 2005;43:4363–4368.

norA Gene

  • norA gene is an antibiotic resistance gene coding for efflux pump that confers resistance against quinolones and fluoroquinolones to bacterial strains containing it. It is extensively identified in MDR (Multi-drug resistant) strains of Staphylococcus aureus and S. epidermidis. norA gene is mainly found in SmaI D fragment of chromosomal DNA in S. aureus, but are also seen in plasmid DNA in some bacteria. It is an 1164 bp long gene with three different genetic variabilities forming three norA variants; norAI, norAII, and norAIII. 
  • norA gene confers higher resistance against hydrophilic quinolones like ofloxacin, norfloxacin, ciprofloxacin, etc. but comparatively lower resistance against hydrophobic quinolones like nalidixic acid, sparfloxacin, oxolinic acid, etc. Beside quinolones and fluoroquinolones, the norA gene is also responsible for the efflux of quaternary ammonium compounds, acriflavine, rhodamine, fusaric acid, etc.   

Mechanism of Conferring Resistance of norA Gene

  • norA gene provides an efflux-based resistance mechanism against quinolones. norA gene codes for the formation of a multidrug resistance efflux pump (norA efflux pump) which uses proton motive forces to expel the quinolones and fluoroquinolones as well as other antibiotic agents from the bacterial cell.  

Detection Method of norA Gene

  • PCR still remains as the most important detection tool for the identification of the norA gene in S. aureus. Some primers used for this purpose are:
PrimersReferences
F: 5´- GAGGGGATCCTATGAATAAACAGA-3´

R: 5´-GCCGAATTCCGCCATATTTTGTTC-3´
Yu JL, Grinius L, Hooper DC. NorA functions as a multidrug efflux protein in both cytoplasmic membrane vesicles and reconstituted proteoliposomes. Journal of Bacteriology. 2002 Mar;184(5):1370-1377. DOI: 10.1128/jb.184.5.1370-1377.2002. PMID: 11844766; PMCID: PMC134835.
F: 5´- TGTTAAGTCTTGGTCATCTGCA-3´

R: 5´- CCATAAATCCACCAATCCC-3´
Couto, I., Costa, S. S., Viveiros, M., Martins, M., and Amaral, L. (2008). Efflux-mediated response of Staphylococcus aureus exposed to ethidium bromide. J. Antimicrob. Chemother. 62, 504–513. doi: 10.1093/jac/dkn217
F: 5´- GGTCATTATTATATTCAGTTGTTG-3´

R: 5´-GTAAGAAAAACGATGCTAAT-3´
Schmitz, F. J., Hertel, B., Hofmann, B., Scheuring, S., Verhoef, J., Fluit, A. C., et al. (1998). Relationship between mutations in the coding and promoter regions of the norA genes in 42 unrelated clinical isolates of Staphylococcus aureus and the MICs of norfloxacin for these strains. J. Antimicrob. Chemother. 42, 561–563. doi: 10.1093/jac/42.4.561

erm Gene

  • Erythromycin ribosomal methylase (erm) gene is an antibiotic resistance gene conferring resistance to bacteria against MLS antibiotics. MSL antibiotics include: (i) macrolides (like erythromycin, azithromycin, clarithromycin, etc.),(ii) lincosamides (like clindamycin, lincomycin, etc.), and (iii) streptogramins (like pristinamycin, virginiamycin, etc.). 
  • Almost all of the Staphylococcus aureus resistant to erythromycin and other MSL antibiotics contain the erm gene in them. It is mainly reported in MDR strains of Staphylococcus including MRSA strains making the infections caused by them more difficult to treat. Besides, the erm gene is also commonly found in other Staphylococcus species and Streptococcus species
  • Several variants of the erm gene have been deposited in gene banks. Some of the published variants are ermA, ermB, ermC, ermD, ermF, ermQ, ermSF, ermTR, ermGT, ermG, ermJ, ermK,ermY, etc. Some of these are plasmid genes while some are found in chromosomal DNA. In Staphylococcus species, ermA,  ermB, and ermC are the most extensively reported variants of erm gene. 

Mechanism of Conferring Resistance of erm Gene

  • erm genes confer resistance against MSL antibiotics by modifying the target site, the bacterial ribosome. 
  • MSL antibiotics inhibit bacterial protein synthesis by preventing peptidyl transferase from elongating the growing peptide chain and also by inhibiting ribosomal translation in bacteria.
  • 23S rRNA methylase mediated by the erm genes modifies the ribosome. The proteins encoded by erm gene methylates the adenine residues (A2058/2059) in the peptidyl transferase region of the 23S rRNA domain of bacterial ribosome. These modified peptidyl transferases prevent the binding of MSL antibiotics and are not inhibited by them, hence bacteria can thrive even in presence of such antibiotics. 

Detection Method of erm Gene

  • As for any other gene, PCR remains the only available effective tool for the detection of erm genes in Staphylococcus chromosomes. The primers that can be used in PCR are:
erm gene typesPrimersReferences
ermA geneF: 5´-GTTCAAGAACAATCAATACAGAG-3´

R: 5´-GGATCAGGAAAAGGACATTTTAC-3´
Salih, Makarem & Abdalla, Alsadig & Masri, Mai & Masri, Rahman. (2014). Detection of Erythromycin Resistance Genes erm(A), erm(B), erm (C) and msr(A) in Staphylococcus Nasal carriers in Khartoum State. 12.
ermA geneF: 5′-AAGCGGTAAACCCCTCTGA-3´ 

R: 5′-TTCGCAAATCCCTTCTCAAC-3´
Inducible clindamycin resistance and erm genes in Staphylococcus aureus in school children in Kathmandu, NepalRoshan Timsina, Upasana Shrestha, Anjana Singh, and Bivek TimalsinaFuture Science OA 2021 7:1
ermB geneF: 5´-CCGTTTACGAAATTGGAACAGGTAAAGGGC-3´

R: 5´-GAATCGAGACTTGAGTGTGC-3´
Salih, Makarem & Abdalla, Alsadig & Masri, Mai & Masri, Rahman. (2014). Detection of Erythromycin Resistance Genes erm(A), erm(B), erm (C) and msr(A) in Staphylococcus Nasal carriers in Khartoum State. 12.
ermB geneF: 5′-CATTTAACGACGAAACTGGC-3′

R: 5′-GGAACATCTGTGGTATGGCG-3′ 
Inducible clindamycin resistance and erm genes in Staphylococcus aureus in school children in Kathmandu, NepalRoshan Timsina, Upasana Shrestha, Anjana Singh, and Bivek TimalsinaFuture Science OA 2021 7:1
ermC geneF: 5′-AATCGTCAATTCCTGCATGT-3′

R: 5′-TAATCGTGGAATACGGGTTTG-3′
Inducible clindamycin resistance and erm genes in Staphylococcus aureus in school children in Kathmandu, NepalRoshan Timsina, Upasana Shrestha, Anjana Singh, and Bivek TimalsinaFuture Science OA 2021 7:1
ermC geneF: 5′-AATTGGCTCAGGAAAAGGGC-3′

R: 5′-AAATCGTCAATTCCCGCATG-3′
 Survey of ermA, ermB, ermC and mecA genes among Staphylococcus aureus isolates isolated from patients admitted to hospitals in Tehran, Iran by PCR and Sequencing (alliedacademies.org)DOI: 10.35841/biomedicalresearch.30-18-1152

msr(A) Gene

  • msr(A) is an antibiotic-resistant gene found exclusively in Staphylococcus spp. that provides the bacterium resistance against macrolides.
  • msr(A) gene is found on mobile elements of the Staphylococcal chromosome and plasmid and mainly protects the bacteria from erythromycin and streptogramin-B. It is the predominant gene in the msr gene family. 
  • Though it is mainly reported in Staphylococcus aureus, the msr(A) gene has also been found in other species of Staphylococcus, Streptococcus, Enterococcus, Pseudomonas, and other Gram-negative bacteria.

Mechanism of Conferring Resistance of msr(A) Gene

  • msr(A) gene also provides efflux-based resistance to Staphylococcus spp. and other bacteria.  
  • msr(A) gene codes for efflux pump (or ATP transporter) called msr(A) efflux pump, which expels the MSL antibiotics (erythromycin and streptogramin-B) from the cell by using the energy derived from ATP hydrolysis.
  • Thus, Staphylococcus strains containing this gene don’t allow MSL antibiotics to accumulate in the cytoplasm and interact with the bacterial ribosomes. Hence, they exert higher tolerance to such antibiotics.

Detection Method of msr(A) Gene

  • Detection of the msr(A) gene relies on the PCR method using the following primers (other primers can also be used): 
PrimersReferences
F: 5′-GGC ACA ATA AGA GTG TTT AAA GG-3′
R: 5′-AAG TTA TAT CAT GAA TAG ATT GTC CTG TT-3′
Ojo, K. K., Striplin, M. J., Ulep, C. C., Close, N. S., Zittle, J., Luis, H., Bernardo, M., Leitao, J., & Roberts, M. C. (2006).
Staphylococcus Efflux msr(A) Gene Characterized in Streptococcus, Enterococcus, Corynebacterium, and Pseudomonas Isolates.
Antimicrobial Agents and Chemotherapy, 50(3), 1089-1091. https://doi.org/10.1128/AAC.50.3.1089-1091.2006

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Prashant Dahal

Prashant Dahal completed his bachelor’s degree (B.Sc.) Microbiology from Sunsari Technical College, affiliated with Tribhuvan University. He is interested in topics related to Antimicrobial resistance, the mechanism of resistance development, Infectious diseases (Pneumonia, tuberculosis, HIV, malaria, dengue), Host-pathogen interaction, Actinomycetes, fungal metabolites, and phytochemicals as novel sources of antimicrobials and Vaccines.

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