Structural and metabolic responses of <i>Staphylococcus aureus</i> biofilms to hyperosmotic and antibiotic stress

Kiamco, Mia Mae; Mohamed, Abdelrhman; Reardon, Patrick N.; Marean‐Reardon, Carrie; Aframehr, Wrya Mohammadi; Call, Douglas R.; Beyenal, Haluk; Renslow, Ryan

doi:10.1002/bit.26572

Cited by 13 publications

(6 citation statements)

References 48 publications

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“…A possible explanation for this observation is that antibiotic-damaged cells may continue to exhibit anabolic activity for some time, even as long as 24 h, although they are incapable of forming a visible colony on an agar plate. Other researchers have reported continued bacterial respiration following aggressive antimicrobial treatment (103)(104)(105)(106)(107)(108).…”

Section: Discussionmentioning

confidence: 97%

Conceptual Model of Biofilm Antibiotic Tolerance That Integrates Phenomena of Diffusion, Metabolism, Gene Expression, and Physiology

et al. 2019

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Transcriptomic, metabolomic, physiological, and computational modeling approaches were integrated to gain insight into the mechanisms of antibiotic tolerance in an in vitro biofilm system. Pseudomonas aeruginosa biofilms were grown in drip flow reactors on a medium composed to mimic the exudate from a chronic wound. After 4 days, the biofilm was 114 μm thick with 9.45 log10 CFU cm−2. These biofilms exhibited tolerance, relative to exponential-phase planktonic cells, to subsequent treatment with ciprofloxacin. The specific growth rate of the biofilm was estimated via elemental balances to be approximately 0.37 h−1 and with a reaction-diffusion model to be 0.32 h−1, or one-third of the maximum specific growth rate for planktonic cells. Global analysis of gene expression indicated lower transcription of ribosomal genes and genes for other anabolic functions in biofilms than in exponential-phase planktonic cells and revealed the induction of multiple stress responses in biofilm cells, including those associated with growth arrest, zinc limitation, hypoxia, and acyl-homoserine lactone quorum sensing. Metabolic pathways for phenazine biosynthesis and denitrification were transcriptionally activated in biofilms. A customized reaction-diffusion model predicted that steep oxygen concentration gradients will form when these biofilms are thicker than about 40 μm. Mutant strains that were deficient in Psl polysaccharide synthesis, the stringent response, the stationary-phase response, and the membrane stress response exhibited increased ciprofloxacin susceptibility when cultured in biofilms. These results support a sequence of phenomena leading to biofilm antibiotic tolerance, involving oxygen limitation, electron acceptor starvation and growth arrest, induction of associated stress responses, and differentiation into protected cell states. IMPORTANCE Bacteria in biofilms are protected from killing by antibiotics, and this reduced susceptibility contributes to the persistence of infections such as those in the cystic fibrosis lung and chronic wounds. A generalized conceptual model of biofilm antimicrobial tolerance with the following mechanistic steps is proposed: (i) establishment of concentration gradients in metabolic substrates and products; (ii) active biological responses to these changes in the local chemical microenvironment; (iii) entry of biofilm cells into a spectrum of states involving alternative metabolisms, stress responses, slow growth, cessation of growth, or dormancy (all prior to antibiotic treatment); (iv) adaptive responses to antibiotic exposure; and (v) reduced susceptibility of microbial cells to antimicrobial challenges in some of the physiological states accessed through these changes.

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Section: Discussionmentioning

confidence: 97%

Conceptual Model of Biofilm Antibiotic Tolerance That Integrates Phenomena of Diffusion, Metabolism, Gene Expression, and Physiology

et al. 2019

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“…Firstly, the light may not have been able to penetrate the biofilms, hence no further antibiofilm effects were observed after PD activation. Secondly, lower oxygen levels within in vitro S. aureus biofilms, ( Kiamco et al., 2018 ) may reduce ROS generation. As ROS production is the mechanism by which PD action acts, ( Maisch et al., 2005 ) an anaerobic environment would limit such effects.…”

Section: Discussionmentioning

confidence: 99%

Antibacterial and Antibiofilm Potency of XF Drugs, Impact of Photodynamic Activation and Synergy With Antibiotics

Board-Davies

Rhys‐Williams²,

Hynes³

et al. 2022

Front. Cell. Infect. Microbiol.

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With increasing incidence of antimicrobial resistance, there is an urgent need for novel and effective antibacterials. Destiny Pharma plc have developed a series of porphyrin-based XF drugs, some with dual mechanisms of antibacterial action. An innate mechanism acts through binding to the outer bacterial membrane and a separate, light-activated, photodynamic (PD) mechanism, acts via the generation of reactive oxygen species. This study aimed to assess the innate and PD associated antibacterial activity of XF drugs against planktonic bacteria, their biofilms and combinational effects with conventional antibiotics. Minimum inhibitory concentrations (MICs) were determined for 3 XF drugs against 114 bacterial isolates. MICs for XF-73 and XF-70 were determined (± PD). DPD-207 was designed to not exhibit PD action due to its structure. XF-drugs (± PD) were further assessed for synergy with conventional antibiotics (using a checkerboard assay) and antibiofilm activity against susceptible strains. XF drugs were innately active against all tested Gram-positive isolates. PD action significantly increased bacterial susceptibility to XF-73 and XF-70 for all Gram-positive isolates. Generally, the XF drugs exhibited higher MICs against Gram-negative isolates, however PD significantly enhanced potency, particularly for XF-70. XF-73 and XF-70 exhibited synergy with ertapenem against a methicillin resistant Staphylococcus aureus (MRSA) strain (± PD) and XF-73 with polymyxin B (± PD) against Pseudomonas aeruginosa. No antagonism was seen between the XF drugs and any of the 5 antibiotics tested. The antibiofilm effect of XF drugs was also observed for all Staphylococcus isolates tested. Generally, PD did not enhance activity for other bacterial isolates tested with the exception of XF-73 against Acinetobacter baumannii biofilms. XF drugs exhibited significant antimicrobial activity against Gram-positive bacteria, with PD enhancement of bacterial susceptibility. Additionally, XF drugs displayed synergy with conventional antibiotics and demonstrated antibiofilm effects.

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“…By studying it directly, unique snapshots of underlying physiological processes can be obtained. Metabolomics has grown in recent years as a powerful tool both for complementing other omics studies and for investigating the immense metabolic diversity found in prokaryotes (Stipetic et al, 2016;Kiamco et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Metabolomics Study Reveals Inhibition and Metabolic Dysregulation in Staphylococcus aureus Planktonic Cells and Biofilms Induced by Carnosol

Shen

Yuan

2020

Front. Microbiol.

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Staphylococcus aureus (S. aureus) is a global health threat accompanied by increasing in drug resistance. To combat this challenge, there is an urgent need to find alternative antimicrobial agents against S. aureus. This study investigated the antimicrobial efficacy of carnosol against S. aureus using an in vitro model. The effects of carnosol were determined based on the antimicrobial effects or formation and disruption of biofilms. Finally, metabolomics of S. aureus grown as planktonic cells and biofilms with carnosol treatment were analyzed using gas chromatography-mass spectrometry. The minimum inhibitory concentrations (MICs) of carnosol were 32 to 256 µg/mL against the sixteen tested S. aureus strains. Among the biofilms, we observed a reduction in bacterial motility of the S. aureus, biofilm development and preformed biofilm after carnosol treatment. Moreover, the significantly altered metabolic pathways upon carnosol treatment in S. aureus planktonic cells and biofilms were highly associated with the perturbation of glyoxylate and dicarboxylate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, and aminoacyl-tRNA biosynthesis. In addition, glutathione metabolism, D-glutamine and D-glutamate metabolism were significantly changed in the biofilms. This study establishes the antibacterial and antibiofilm properties of carnosol, and will provide an alternative strategy for overcoming the drug resistance of S. aureus.

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Structural and metabolic responses of Staphylococcus aureus biofilms to hyperosmotic and antibiotic stress

Cited by 13 publications

References 48 publications

Conceptual Model of Biofilm Antibiotic Tolerance That Integrates Phenomena of Diffusion, Metabolism, Gene Expression, and Physiology

Conceptual Model of Biofilm Antibiotic Tolerance That Integrates Phenomena of Diffusion, Metabolism, Gene Expression, and Physiology

Antibacterial and Antibiofilm Potency of XF Drugs, Impact of Photodynamic Activation and Synergy With Antibiotics

Metabolomics Study Reveals Inhibition and Metabolic Dysregulation in Staphylococcus aureus Planktonic Cells and Biofilms Induced by Carnosol

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