The Staphylococcus aureus CidA and LrgA Proteins Are Functional Holins Involved in the Transport of By-Products of Carbohydrate Metabolism

Endres, Jennifer L.; Chaudhari, Sujata S.; Zhang, Xinyan; Prahlad, Janani; Wang, Shuqi; Foley, Lily A; Luca, Sorin; Bose, Jeffrey L.; Thomas, Vinai Chittezham; Bayles, Kenneth W.

doi:10.1128/mbio.02827-21

Cited by 18 publications

(15 citation statements)

References 50 publications

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“…Two other genes, lrgA and lrgB, encode holin-like proteins that are regulators of cell death and promote penicillin tolerance . Recently, LrgA has also been shown to help transport carbohydrate metabolism byproducts . Finally, msrA1 and msrB encode cotranscribed peptide methionine sulfoxide reductases.…”

Section: Resultsmentioning

confidence: 99%

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Loratadine Combats Methicillin-Resistant Staphylococcus aureus by Modulating Virulence, Antibiotic Resistance, and Biofilm Genes

Viering,

Balogh,

Cox

et al. 2023

ACS Infect. Dis.

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Methicillin-resistant Staphylococcus aureus (MRSA) has evolved to become resistant to multiple classes of antibiotics. New antibiotics are costly to develop and deploy, and they have a limited effective lifespan. Antibiotic adjuvants are molecules that potentiate existing antibiotics through nontoxic mechanisms. We previously reported that loratadine, the active ingredient in Claritin, potentiates multiple cell-wall active antibiotics in vitro and disrupts biofilm formation through a hypothesized inhibition of the master regulatory kinase Stk1. Loratadine and oxacillin combined repressed the expression of key antibiotic resistance genes in the bla and mec operons. We hypothesized that additional genes involved in antibiotic resistance, biofilm formation, and other cellular pathways would be modulated when looking transcriptome-wide. To test this, we used RNA-seq to quantify transcript levels and found significant effects in gene expression, including genes controlling virulence, antibiotic resistance, metabolism, transcription (core RNA polymerase subunits and sigma factors), and translation (a plethora of genes encoding ribosomal proteins and elongation factor Tu). We further demonstrated the impacts of these transcriptional effects by investigating loratadine treatment on intracellular ATP levels, persister formation, and biofilm formation and morphology. Loratadine minimized biofilm formation in vitro and enhanced the survival of infected Caenorhabditis elegans. These pleiotropic effects and their demonstrated outcomes on MRSA virulence and survival phenotypes position loratadine as an attractive anti-infective against MRSA.

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Section: Resultsmentioning

confidence: 99%

“… 17 Recently, LrgA has also been shown to help transport carbohydrate metabolism byproducts. 18 Finally, msrA1 and msrB encode cotranscribed peptide methionine sulfoxide reductases. These enzymes serve to minimize damage to proteins during oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

Loratadine Combats Methicillin-Resistant Staphylococcus aureus by Modulating Virulence, Antibiotic Resistance, and Biofilm Genes

Viering,

Balogh,

Cox

et al. 2023

ACS Infect. Dis.

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show abstract

“…13 Recently, LrgA has also been shown to help transport carbohydrate metabolism byproducts. 14 Finally, msrA1 and msrB are cotranscribed peptide methionine sulfoxide reductases. These enzymes serve to minimize damage to proteins during oxidative stress.…”

Section: Subcluster Analysis Showed Different Patterns Of Gene Expres...mentioning

confidence: 99%

Transcriptomic Analysis of Loratadine as an Antibiotic Adjuvant Against MRSA

Viering

Balogh

Akers

et al. 2023

Preprint

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Methicillin-resistant Staphylococcus aureus (MRSA) has evolved to become resistant to multiple classes of antibiotics. New antibiotics are costly to develop and deploy, and they have a limited effective lifespan. Antibiotic adjuvants are molecules that potentiate existing antibiotics through non-toxic mechanisms. We previously reported that loratadine, the active ingredient in Claritin potentiates multiple cell-wall active antibiotics in vitro and disrupts biofilm formation through a hypothesized inhibition of the master regulatory kinase Stk1. Loratadine and oxacillin combined repressed the expression of key antibiotic resistance genes in the bla and mec operons. We hypothesized that additional differentially expressed genes involved in antibiotic resistance, biofilm formation, and other cellular pathways would be modulated when looking transcriptome wide. To test this, we used RNA-seq to quantify transcript levels and found pleiotropic effects in gene expression, including genes implicated in antibiotic resistance, as well as genes critical for metabolism, transcription (RNA Polymerase subunits alpha and beta), and translation (a plethora of ribosomal protein genes and Elongation Factor Tu). Stk1 and its cognate phosphatase, stp, were also downregulated by loratadine. Together, this provides the most molecular details to date about loratadine’s function as an antibiotic adjuvant.

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“…Holins can be categorized as canonical holin endolysins resulting in pores between 35 and 340 nm and a pinhole SAR (signal-arrest-release) endolysin resulting in 2-nm pores. Given the system used to demonstrate holin activity, Endres et al suggest CidA and LrgA to be members of the former canonical category ( 2 ).…”

Section: Commentarymentioning

confidence: 99%

“…Furthermore, the holin activities of CidA and LrgA are predicted to influence membrane depolarization and disruption of the proton motive force, resulting in an increase in localized pH triggering murein hydrolase activity and lysis. In their most recent work, Endres et al ( 2 ) discuss lrgAB in the context of Bacillus subtilis and Streptococcus mutans lrgAB operons, where they function as intracellular pyruvate regulators, and one may hypothesize that LrgAB-mediated pyruvate shuttling feeds into the above systems, where excess carbon flow transported by lrgAB regulates cell death via modulation of intracellular acidification and dissipation of the cell membrane potential. The role of acetic acid as an inducer of cellular change analogous to eukaryotic apoptosis was previously seen in yeast species ( 6 ).…”

Section: Commentarymentioning

confidence: 99%

CidA and LrgA: a “Hole” Lot More than Programmed Cell Death

Laabei

Duggan

2022

mBio

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What do programmed cell death (PCD) and carbohydrate metabolism by-product transport have in common? Intriguingly, both processes involve the cidABC and lrgAB operons in the major human pathogen Staphylococcus aureus . Previously, CidA and LrgA have been studied in the context of programmed cell death, but a second function in overflow metabolism is increasingly evident.

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The Staphylococcus aureus CidA and LrgA Proteins Are Functional Holins Involved in the Transport of By-Products of Carbohydrate Metabolism

Cited by 18 publications

References 50 publications

Loratadine Combats Methicillin-Resistant Staphylococcus aureus by Modulating Virulence, Antibiotic Resistance, and Biofilm Genes

Loratadine Combats Methicillin-Resistant Staphylococcus aureus by Modulating Virulence, Antibiotic Resistance, and Biofilm Genes

Transcriptomic Analysis of Loratadine as an Antibiotic Adjuvant Against MRSA

CidA and LrgA: a “Hole” Lot More than Programmed Cell Death

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