Genetic Diversity of norA, Coding for a Main Efflux Pump of Staphylococcus aureus

Costa, SS; Sobkowiak, Benjamin; Parreira, Ricardo; Edgeworth, Jonathan D; Viveiros, Miguel; Clark, Taane G.; Couto, Isabel

doi:10.3389/fgene.2018.00710

Cited by 74 publications

(58 citation statements)

References 61 publications

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“…no pre-mature stop codons or frameshift mutations). In line with previous work 45 , we found that the norA coding sequence is polymorphic, and we identified polymorphisms in a previously characterized norA promoter region 46 – 48 . However, the P values associated with these polymorphisms are 1000 times higher than the conservative significance threshold used in our GWAS analysis, suggesting that these associations are true negatives.…”

Section: Resultssupporting

confidence: 90%

Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates

et al. 2020

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The rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. Here, we test this hypothesis by challenging a diverse set of 222 isolates of Staphylococcus aureus with the antibiotic ciprofloxacin in a large-scale evolution experiment. We find that a single efflux pump, norA, causes widespread variation in evolvability across isolates. Elevated norA expression potentiates evolution by increasing the fitness benefit provided by DNA topoisomerase mutations under ciprofloxacin treatment. Amplification of norA provides a further mechanism of rapid evolution in isolates from the CC398 lineage. Crucially, chemical inhibition of NorA effectively prevents the evolution of resistance in all isolates. Our study shows that pre-existing genetic diversity plays a key role in shaping resistance evolution, and it may be possible to predict which strains are likely to evolve resistance and to optimize inhibitor use to prevent this outcome.

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Section: Resultssupporting

confidence: 90%

Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates

et al. 2020

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“…This finding suggests a delicate balance in the tolerable expression levels of norA, which, in turn, places a theoretical limit to the degree of norA overexpression-mediated resistance that can occur in a strain. Beyond norA expression, it is worth mentioning that a recent report defined three possible norA alleles (17). It is intriguing to speculate that these various alleles may have different functional consequences in terms of norAmediated antiseptic resistance; however, this topic remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned above, norA was recently described as part of the core genome of S. aureus, but was shown to exist as multiple possible alleles (17). norA is known to impart resistance to a variety of structurally diverse compounds, and previous work suggests that NorA may be responsible for the majority of basal antiseptic resistance in S. aureus (37,38).…”

mentioning

confidence: 94%

“…In S. aureus, the antiporter efflux pumps QacA, NorA, and QacC are known to offer increased resistance to a wide range of common antiseptics (16). Besides norA, which has recently been shown to be part of the core genome of S. aureus (17), qacA and qacC reside on a variety of conjugative and nonconjugative plasmids (18,19). The majority of qac prevalence studies demonstrate that while qacA and qacC do not commonly coexist within S. aureus, the presence of all three efflux pumps within S. aureus isolates does occur (20)(21)(22); however, the functional consequences of harboring all three pumps are unknown.…”

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confidence: 99%

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Systematic Analysis of Efflux Pump-Mediated Antiseptic Resistance in Staphylococcus aureus Suggests a Need for Greater Antiseptic Stewardship

LaBreck

Bochi-Layec

Stanbro

et al. 2020

mSphere

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Staphylococcus aureus-associated infections can be difficult to treat due to multidrug resistance. Thus, infection prevention is critical. Cationic antiseptics, such as chlorhexidine (CHX) and benzalkonium chloride (BKC), are liberally used in health care and community settings to prevent infection. However, increased administration of antiseptics has selected for S. aureus strains that show reduced susceptibilities to cationic antiseptics. This increased resistance has been associated with carriage of specific efflux pumps (QacA, QacC, and NorA). Since prior published studies focused on different strains and on strains carrying only a single efflux gene, the relative importance of these various systems to antiseptic resistance is difficult to ascertain. To overcome this, we engineered a collection of isogenic S. aureus strains that harbored norA, qacA, and qacC, individually or in combination. MIC assays showed that qacA was associated with increased resistance to CHX, cetrimide (CT), and BKC, qacC was associated with resistance to CT and BKC, and norA was necessary for basal-level resistance to the majority of tested antiseptics. When all three pumps were present in a single strain, an additive effect was observed in the MIC for CT. Transcriptional analysis revealed that expression of qacA and norA was significantly induced following exposure to BKC. Alarmingly, in a strain carrying qacA and norA, preexposure to BKC increased CHX tolerance. Overall, our results reveal increased antiseptic resistance in strains carrying multiple efflux pumps and indicate that preexposure to BKC, which is found in numerous daily-use products, can increase CHX tolerance. IMPORTANCE S. aureus remains a significant cause of disease within hospitals and communities. To reduce the burden of S. aureus infections, antiseptics are ubiquitously used in our daily lives. Furthermore, many antiseptic compounds are dual purpose and are found in household products. The increased abundance of antiseptic compounds has selected for S. aureus strains that carry efflux pumps that increase resistance to antiseptic compounds; however, the effect of carrying multiple pumps within S. aureus is unclear. We demonstrated that an isogenic strain carrying multiple efflux pumps had an additive resistance phenotype to cetrimide. Moreover, in a strain carrying qacA and norA, increased chlorhexidine tolerance was observed after the strain was preexposed to subinhibitory concentrations of a different common-use antiseptic. Taken together, our findings demonstrate cooperation between antiseptic resistance efflux pumps and suggest that their protective phenotype may be exacerbated by priming with subinhibitory concentrations of household antiseptics.

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“…When induced by substrates in the environment for a long time, efflux system-encoding genes are activated and expressed, and the ability to efflux drugs is greatly enhanced, thus leading to drug resistance (Zarate et al, 2019). Active drug efflux systems play a role in resistance to multiple drugs (Costa et al, 2018). There are three types of multidrugpumping proteins present on the Staphylococcus aureus cell membrane: QacA, NorA, and Smr (Foster, 2016;Jang, 2016).…”

Section: Efflux Systemsmentioning

confidence: 99%

Prevalence and Therapies of Antibiotic-Resistance in Staphylococcus aureus

Guo

Song

Sun

et al. 2020

Front. Cell. Infect. Microbiol.

521

350

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Infectious diseases are the second most important cause of human death worldwide; Staphylococcus aureus (S. aureus) is a very common human pathogenic microorganism that can trigger a variety of infectious diseases, such as skin and soft tissue infections, endocarditis, osteomyelitis, bacteremia, and lethal pneumonia. Moreover, according to the sensitivity to antibiotic drugs, S. aureus can be divided into methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). In recent decades, due to the evolution of bacteria and the abuse of antibiotics, the drug resistance of S. aureus has gradually increased, the infection rate of MRSA has increased worldwide, and the clinical anti-infective treatment for MRSA has become more difficult. Accumulating evidence has demonstrated that the resistance mechanisms of S. aureus are very complex, especially for MRSA, which is resistant to many kinds of antibiotics. Therefore, understanding the drug resistance of MRSA in a timely manner and elucidating its drug resistance mechanism at the molecular level are of great significance for the treatment of S. aureus infection. A large number of researchers believe that analyzing the molecular characteristics of S. aureus can help provide a basis for designing effective prevention and treatment measures against hospital infections caused by S. aureus and further monitor the evolution of S. aureus. This paper reviews the research status of MSSA and MRSA, the detailed mechanisms of the intrinsic antibiotic resistance and the acquired antibiotic resistance, the advanced research on anti-MRSA antibiotics and novel therapeutic strategies for MRSA treatment.

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Genetic Diversity of norA, Coding for a Main Efflux Pump of Staphylococcus aureus

Cited by 74 publications

References 61 publications

Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates

Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates

Systematic Analysis of Efflux Pump-Mediated Antiseptic Resistance in Staphylococcus aureus Suggests a Need for Greater Antiseptic Stewardship

Prevalence and Therapies of Antibiotic-Resistance in Staphylococcus aureus

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