Pharmacodynamic Evaluation of the Activity of Antibiotics Against Hemin- and Menadione-dependent Small-colony Variants of Staphylococcus Aureus in Models of Extracellular (broth) and Intracellular (THP-1 Monocytes) Infections

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2012 May 9

PMID 22564838

Citations 19

Authors

L G Garcia

S Lemaire

B C Kahl

K Becker

R A Proctor

O Denis

P M Tulkens

F Van Bambeke

Affiliations

Soon will be listed here.

Abstract

Staphylococcus aureus small-colony variants (SCVs) persist intracellularly, which may contribute to persistence/recurrence of infections and antibiotic failure. We have studied the intracellular fate of menD and hemB mutants (corresponding to menadione- and hemin-dependent SCVs, respectively) of the COL methicillin-resistant S. aureus (MRSA) strain and the antibiotic pharmacodynamic profile against extracellular (broth) and intracellular (human THP-1 monocytes) bacteria. Compared to the parental strain, SCVs showed slower extracellular growth (restored upon medium supplementation with menadione or hemin), reduced phagocytosis, and, for the menD SCV, lower intracellular counts at 24 h postinfection. Against extracellular bacteria, daptomycin, gentamicin, rifampin, moxifloxacin, and oritavancin showed similar profiles of activity against all strains, with a static effect obtained at concentrations close to their MICs and complete eradication as maximal effect. In contrast, vancomycin was not bactericidal against SCVs. Against intracellular bacteria, concentration-effect curves fitted sigmoidal regressions for vancomycin, daptomycin, gentamicin, and rifampin (with maximal effects lower than a 2-log decrease in CFU) but biphasic regressions (with a maximal effect greater than a 3-log decrease in CFU) for moxifloxacin and oritavancin, suggesting a dual mode of action against intracellular bacteria. For all antibiotics, these curves were indistinguishable between the strains investigated, except for the menD mutant, which systematically showed a lower amplitude of the concentration-effect response, with markedly reduced minimal efficacy (due to slower growth) but no change in maximal efficacy. The data therefore show that the maximal efficacies of antibiotics are similar against normal-phenotype and menadione- and hemin-dependent strains despite their different intracellular fates, with oritavancin, and to some extent moxifloxacin, being the most effective.

Citing Articles

New Antimicrobials and New Therapy Strategies for Endocarditis: Weapons That Should Be Defended.

Oliva A, Cogliati Dezza F, Cancelli F, Curtolo A, Falletta A, Volpicelli L J Clin Med. 2023; 12(24).

PMID: 38137762 PMC: 10743892. DOI: 10.3390/jcm12247693.

Involvement of Small Colony Variant-Related Heme Biosynthesis Genes in Persister Formation .

Wang X, Li W, Wang W, Wang S, Xu T, Chen J Front Microbiol. 2022; 12:756809.

PMID: 35003000 PMC: 8733728. DOI: 10.3389/fmicb.2021.756809.

Characteristics of Staphylococcus aureus small colony variants isolated from wound specimen of a tertiary care hospital in China.

Min C, Wang H, Xia F, Tang M, Li J, Hu Y J Clin Lab Anal. 2021; 36(1):e24121.

PMID: 34837244 PMC: 8761406. DOI: 10.1002/jcla.24121.

Heme-Dependent Siderophore Utilization Promotes Iron-Restricted Growth of the Staphylococcus aureus Small-Colony Variant.

Batko I, Flannagan R, Guariglia-Oropeza V, Sheldon J, Heinrichs D J Bacteriol. 2021; 203(24):e0045821.

PMID: 34606375 PMC: 8604074. DOI: 10.1128/JB.00458-21.

Ginsenoside 20(S)-Rh2 promotes cellular pharmacokinetics and intracellular antibacterial activity of levofloxacin against Staphylococcus aureus through drug efflux inhibition and subcellular stabilization.

Chen X, Qian F, Wang Y, Liu Y, Sun Y, Zha W Acta Pharmacol Sin. 2021; 42(11):1930-1941.

PMID: 34462563 PMC: 8564512. DOI: 10.1038/s41401-021-00751-z.

References

von Eiff C, Heilmann C, Proctor R, Woltz C, Peters G, Gotz F . A site-directed Staphylococcus aureus hemB mutant is a small-colony variant which persists intracellularly. J Bacteriol. 1997; 179(15):4706-12. PMC: 179315. DOI: 10.1128/jb.179.15.4706-4712.1997. View

Takemura H, Yamamoto H, Kunishima H, Ikejima H, Hara T, Kanemitsu K . Evaluation of a human monocytic cell line THP-1 model for assay of the intracellular activities of antimicrobial agents against Legionella pneumophila. J Antimicrob Chemother. 2000; 46(4):589-94. DOI: 10.1093/jac/46.4.589. View

Scorneaux B, Ouadrhiri Y, Anzalone G, Tulkens P . Effect of recombinant human gamma interferon on intracellular activities of antibiotics against Listeria monocytogenes in the human macrophage cell line THP-1. Antimicrob Agents Chemother. 1996; 40(5):1225-30. PMC: 163296. DOI: 10.1128/AAC.40.5.1225. View

Vesga O, Groeschel M, Otten M, Brar D, Vann J, Proctor R . Staphylococcus aureus small colony variants are induced by the endothelial cell intracellular milieu. J Infect Dis. 1996; 173(3):739-42. DOI: 10.1093/infdis/173.3.739. View

Schwende H, Fitzke E, Ambs P, Dieter P . Differences in the state of differentiation of THP-1 cells induced by phorbol ester and 1,25-dihydroxyvitamin D3. J Leukoc Biol. 1996; 59(4):555-61. View

Mascio C, Alder J, Silverman J . Bactericidal action of daptomycin against stationary-phase and nondividing Staphylococcus aureus cells. Antimicrob Agents Chemother. 2007; 51(12):4255-60. PMC: 2167999. DOI: 10.1128/AAC.00824-07. View

Proctor R, Kahl B, von Eiff C, Vaudaux P, Lew D, Peters G . Staphylococcal small colony variants have novel mechanisms for antibiotic resistance. Clin Infect Dis. 1998; 27 Suppl 1:S68-74. DOI: 10.1086/514906. View

Baba-Moussa L, Anani L, Scheftel J, Couturier M, Riegel P, Haikou N . Virulence factors produced by strains of Staphylococcus aureus isolated from urinary tract infections. J Hosp Infect. 2007; 68(1):32-8. DOI: 10.1016/j.jhin.2007.10.010. View

Ghigo E, Capo C, Tung C, Raoult D, Gorvel J, Mege J . Coxiella burnetii survival in THP-1 monocytes involves the impairment of phagosome maturation: IFN-gamma mediates its restoration and bacterial killing. J Immunol. 2002; 169(8):4488-95. DOI: 10.4049/jimmunol.169.8.4488. View

10.

Mates S, Eisenberg E, Mandel L, Patel L, Kaback H, Miller M . Membrane potential and gentamicin uptake in Staphylococcus aureus. Proc Natl Acad Sci U S A. 1982; 79(21):6693-7. PMC: 347195. DOI: 10.1073/pnas.79.21.6693. View

11.

Kahl B, Duebbers A, Lubritz G, Haeberle J, Koch H, Ritzerfeld B . Population dynamics of persistent Staphylococcus aureus isolated from the airways of cystic fibrosis patients during a 6-year prospective study. J Clin Microbiol. 2003; 41(9):4424-7. PMC: 193812. DOI: 10.1128/JCM.41.9.4424-4427.2003. View

12.

Lemaire S, Kosowska-Shick K, Appelbaum P, Verween G, Tulkens P, Van Bambeke F . Cellular pharmacodynamics of the novel biaryloxazolidinone radezolid: studies with infected phagocytic and nonphagocytic cells, using Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, and Legionella pneumophila. Antimicrob Agents Chemother. 2010; 54(6):2549-59. PMC: 2876393. DOI: 10.1128/AAC.01724-09. View

13.

Karauzum H, Ferry T, de Bentzmann S, Lina G, Bes M, Vandenesch F . Comparison of adhesion and virulence of two predominant hospital-acquired methicillin-resistant Staphylococcus aureus clones and clonal methicillin-susceptible S. aureus isolates. Infect Immun. 2008; 76(11):5133-8. PMC: 2573375. DOI: 10.1128/IAI.01697-07. View

14.

Van Bambeke F, Van Laethem Y, Courvalin P, Tulkens P . Glycopeptide antibiotics: from conventional molecules to new derivatives. Drugs. 2004; 64(9):913-36. DOI: 10.2165/00003495-200464090-00001. View

15.

Barcia-Macay M, Lemaire S, Mingeot-Leclercq M, Tulkens P, Van Bambeke F . Evaluation of the extracellular and intracellular activities (human THP-1 macrophages) of telavancin versus vancomycin against methicillin-susceptible, methicillin-resistant, vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2006; 58(6):1177-84. DOI: 10.1093/jac/dkl424. View

16.

Liu C, Bayer A, Cosgrove S, Daum R, Fridkin S, Gorwitz R . Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011; 52(3):285-92. DOI: 10.1093/cid/cir034. View

17.

Zhou H, Deloid G, Browning E, Gregory D, Tan F, Bedugnis A . Genome-wide RNAi screen in IFN-γ-treated human macrophages identifies genes mediating resistance to the intracellular pathogen Francisella tularensis. PLoS One. 2012; 7(2):e31752. PMC: 3281001. DOI: 10.1371/journal.pone.0031752. View

18.

Van Bambeke F, Barcia-Macay M, Lemaire S, Tulkens P . Cellular pharmacodynamics and pharmacokinetics of antibiotics: current views and perspectives. Curr Opin Drug Discov Devel. 2006; 9(2):218-30. View

19.

Vaudaux P, Francois P, Bisognano C, Kelley W, Lew D, Schrenzel J . Increased expression of clumping factor and fibronectin-binding proteins by hemB mutants of Staphylococcus aureus expressing small colony variant phenotypes. Infect Immun. 2002; 70(10):5428-37. PMC: 128368. DOI: 10.1128/IAI.70.10.5428-5437.2002. View

20.

Stokes R, Doxsee D . The receptor-mediated uptake, survival, replication, and drug sensitivity of Mycobacterium tuberculosis within the macrophage-like cell line THP-1: a comparison with human monocyte-derived macrophages. Cell Immunol. 1999; 197(1):1-9. DOI: 10.1006/cimm.1999.1554. View