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A Themed Issue in Honor of Professor Richard Proctor—Outstanding Contributions...
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A Themed Issue in Honor of Professor Richard Proctor—Outstanding Contributions in the Fields of Persistent Staphylococcus aureus Infections

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 19184

Special Issue Editors

Dr. Steven Projan

E-Mail Website
Guest Editor
1. Infectious Diseases & Vaccines Innovative Medicines unit (iMED) at MedImmune, Gaithersburg, MA, USA
2. Novartis Institutes for Biomedical Research, 22 Windsor St, Cambridge, MA 02139, USA
Interests: infectious diseases; vaccines
Prof. Dr. Barbara C. Kahl

E-Mail Website
Guest Editor
Institute of Medical Microbiology, University Hospital of Münster, 48149 Münster, Germany
Interests: staphylococcus aureus; persistent infection; small colony variants (SCVs); thymidine-dependency; epidemiology; cystic fibrosis; neutrophil extracellular traps; mucoidy; biofilm
Prof. Dr. Karsten Becker

E-Mail Website
Guest Editor
Friedrich Loeffler-Institute of Medical Microbiology, University Medicine Greifswald, 17475 Greifswald, Germany
Interests: staphylococci; pathogens; microbiota; epidemiology; multi-drug resistance; one health aspects
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Professor Richard Proctor has significantly contributed to the field of persistent Staphylococcus aureus infections. These studies date back over 35 years, to the examination of ingestion of S. aureus by bovine endothelial cells (Vann JM and Proctor RA. Infect Innum. 55: 2155,1987). The final sentence in the abstract of this paper was prescient as a possible mechanism for persistent bacteremia: “Intracellular S.aureus would be continuously released into the circulation, possibly accounting for the persistent bacteremia that is found in S.aureus endovascular infections.” These studies led to an examination of lysis of endothelial cells by Hla (Vann JM and Proctor RA. Microb Pathogen 4: 443, 1988) and a search for naturally occurring non-lytic strains in the clinic. While we anticipated finding hla mutants, small colony variants (SCVs) were found instead. Of course, this resulted in decades of work on SCVs, with their description as a cause for persistent infections having been summarized in three reviews (Proctor RA et al. Naure Rev Microb 4: 295, 2006; Kahl BC et al. Clin Microb Rev 29: 401-427, 2016; Tuchshurr L et al. Front Microbiol 11: 1028, 2020). The observations that S. aureus was able to enter many types of host cells, hide from the immune system, resist antibiotics because of metabolic changes, and undergo SCV transformation was anticipated in early work; however, the number of mutations and pathways proliferated over the years.

Of course, the complex biology described in these two reviews continues to evolve. Many of the more recent observations are discussed in the papers in this Special Issue. Professor Proctor is justifiably proud of the large number of contributions made by his trainees and notes that this work could not have happened without their creativity and hard work. He would especially like to recognize and remember Professor Georg Peters, who was a close collaborator and dear friend who made so many contributions to the SCV work, especially establishing the clinical characteristics in large studies, then following this up with work on much of the cell biology of persistence. Our labs have worked continuously on this since.

The studies of the biochemical pathways that resulted in SCVs have also shed light on the biochemical pathways that produce antibiotic resistance. Thus, the study of SCVs has resulted in a better understanding of the mechanisms of bacterial antibiotic resistance.

Dr. Steven Projan
Prof. Dr. Barbara C. Kahl
Prof. Dr. Karsten Becker
Guest Editors

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Published Papers (6 papers)

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Research

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19 pages, 1312 KiB  
Article
Staphylococcus aureus Small-Colony Variants from Airways of Adult Cystic Fibrosis Patients as Precursors of Adaptive Antibiotic-Resistant Mutations
by Guillaume Millette, David Lalonde Séguin, Charles Isabelle, Suzanne Chamberland, Jean-François Lucier, Sébastien Rodrigue, André M. Cantin and François Malouin
Antibiotics 2023, 12(6), 1069; https://doi.org/10.3390/antibiotics12061069 - 17 Jun 2023
Cited by 9 | Viewed by 1912
Abstract
Prototypic Staphylococcus aureus and their small-colony variants (SCVs) are predominant in cystic fibrosis (CF), but the interdependence of these phenotypes is poorly understood. We characterized S. aureus isolates from adult CF patients over several years. Of 18 S. aureus-positive patients (58%), 13 [...] Read more.
Prototypic Staphylococcus aureus and their small-colony variants (SCVs) are predominant in cystic fibrosis (CF), but the interdependence of these phenotypes is poorly understood. We characterized S. aureus isolates from adult CF patients over several years. Of 18 S. aureus-positive patients (58%), 13 (72%) were positive for SCVs. Characterization included genotyping, SCCmec types, auxotrophy, biofilm production, antibiotic susceptibilities and tolerance, and resistance acquisition rates. Whole-genome sequencing revealed that several patients were colonized with prototypical and SCV-related clones. Some clonal pairs showed acquisition of aminoglycoside resistance that was not explained by aminoglycoside-modifying enzymes, suggesting a mutation-based process. The characteristics of SCVs that could play a role in resistance acquisition were thus investigated further. For instance, SCV isolates produced more biofilm (p < 0.05) and showed a higher survival rate upon exposure to ciprofloxacin and vancomycin compared to their prototypic associated clones. SCVs also developed spontaneous rifampicin resistance mutations at a higher frequency. Accordingly, a laboratory-derived SCV (ΔhemB) acquired resistance to ciprofloxacin and gentamicin faster than its parent counterpart after serial passages in the presence of sub-inhibitory concentrations of antibiotics. These results suggest a role for SCVs in the establishment of persistent antibiotic-resistant clones in adult CF patients. Full article
(This article belongs to the Special Issue A Themed Issue in Honor of Professor Richard Proctor—Outstanding Contributions in the Fields of Persistent Staphylococcus aureus Infections)
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7 pages, 761 KiB  
Article
Antimicrobial Efficacy against Antibiotic-Tolerant Staphylococcus aureus Depends on the Mechanism of Antibiotic Tolerance
by Emily M. Meredith, Lauren T. Harven and Andrew D. Berti
Antibiotics 2022, 11(12), 1810; https://doi.org/10.3390/antibiotics11121810 - 13 Dec 2022
Cited by 4 | Viewed by 2074
Abstract
Bacteria can adapt to a changing environment by adopting alternate metabolic states favoring small molecule synthesis and resilience over growth. In Staphylococcus aureus, these states are induced by factors present during infection, including nutritional limitations, host responses and competition with other bacteria. [...] Read more.
Bacteria can adapt to a changing environment by adopting alternate metabolic states favoring small molecule synthesis and resilience over growth. In Staphylococcus aureus, these states are induced by factors present during infection, including nutritional limitations, host responses and competition with other bacteria. Isogenic “tolerant” populations have variable responses to antibiotics and can remain viable. In this study, we compared the capability of antibiotics to reduce the viability of S. aureus made tolerant by different mechanisms. Tolerance was induced with mupirocin, HQNO, peroxynitrite or human serum. Tolerant cultures were exposed to ceftaroline, daptomycin, gentamicin, levofloxacin, oritavancin or vancomycin at physiological concentrations, and the viability was assessed by dilution plating. The minimum duration for 3-log viability reduction and 24 h viability reduction were calculated independently for each of three biological replicates. Each tolerance mechanism rendered at least one antibiotic ineffective, and each antibiotic was rendered ineffective by at least one mechanism of tolerance. Further studies to evaluate additional antibiotics, combination therapy and different tolerance inducers are warranted. Full article
(This article belongs to the Special Issue A Themed Issue in Honor of Professor Richard Proctor—Outstanding Contributions in the Fields of Persistent Staphylococcus aureus Infections)
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14 pages, 2597 KiB  
Article
Synchrotron-Radiation-Based Fourier Transform Infrared Microspectroscopy as a Tool for the Differentiation between Staphylococcal Small Colony Variants
by Amal G. Al-Bakri, Lina A. Dahabiyeh, Enam Khalil, Deema Jaber, Gihan Kamel, Nina Schleimer, Christian Kohler and Karsten Becker
Antibiotics 2022, 11(11), 1607; https://doi.org/10.3390/antibiotics11111607 - 11 Nov 2022
Cited by 1 | Viewed by 1584
Abstract
Small colony variants (SCVs) are clinically significant and linked to persistent infections. In this study, synchrotron-radiation-based Fourier transform infrared (SR-FTIR) is used to investigate the microspectroscopic differences between the SCVs of Staphylococcus aureus (S. aureus) and diabetic foot Staphylococcus epidermidis ( [...] Read more.
Small colony variants (SCVs) are clinically significant and linked to persistent infections. In this study, synchrotron-radiation-based Fourier transform infrared (SR-FTIR) is used to investigate the microspectroscopic differences between the SCVs of Staphylococcus aureus (S. aureus) and diabetic foot Staphylococcus epidermidis (S. epidermidis) in two main IR spectral regions: (3050–2800 cm−1), corresponding to the distribution of lipids, and (1855–1500 cm−1), corresponding to the distribution of protein amide I and amide II and carbonyl vibrations. SR-FTIR successfully discriminated between the two staphylococcal species and between the SCV and the non-SCV strains within the two IR spectral regions. Combined S. aureus SCVs (SCVhMu) showed a higher protein content relative to the non-SCV wild type. Complemented S. aureus SCV showed distinguishable differences from the SCVhMu and the wild type, including a higher content of unsaturated fatty acids. An increase in the CH2/CH3 ratio was detected in S. epidermidis SCV samples compared to the standard control. Protein secondary structure in standard S. epidermidis and SCVs consisted mainly of an α-helix; however, a new shoulder at 1635 cm−1, assigned to β-sheets, was evident in the SCV. In conclusion, SR-FTIR is a powerful method that can discriminate between staphylococci species and to differentiate between SCVs and their corresponding natural strains. Full article
(This article belongs to the Special Issue A Themed Issue in Honor of Professor Richard Proctor—Outstanding Contributions in the Fields of Persistent Staphylococcus aureus Infections)
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Review

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13 pages, 1307 KiB  
Review
Detection, Identification and Diagnostic Characterization of the Staphylococcal Small Colony-Variant (SCV) Phenotype
by Karsten Becker
Antibiotics 2023, 12(9), 1446; https://doi.org/10.3390/antibiotics12091446 - 14 Sep 2023
Cited by 5 | Viewed by 3522
Abstract
While modern molecular methods have decisively accelerated and improved microbiological diagnostics, phenotypic variants still pose a challenge for their detection, identification and characterization. This particularly applies if they are unstable and hard to detect, which is the case for the small-colony-variant (SCV) phenotype [...] Read more.
While modern molecular methods have decisively accelerated and improved microbiological diagnostics, phenotypic variants still pose a challenge for their detection, identification and characterization. This particularly applies if they are unstable and hard to detect, which is the case for the small-colony-variant (SCV) phenotype formed by staphylococci. On solid agar media, staphylococcal SCVs are characterized by tiny colonies with deviant colony morphology. Their reduced growth rate and fundamental metabolic changes are the result of their adaptation to an intracellular lifestyle, regularly leading to specific auxotrophies, such as for menadione, hemin or thymidine. These alterations make SCVs difficult to recognize and render physiological, biochemical and other growth-based methods such as antimicrobial susceptibility testing unreliable or unusable. Therefore, diagnostic procedures require prolonged incubation times and, if possible, confirmation by molecular methods. A special approach is needed for auxotrophy testing. However, standardized protocols for SCV diagnostics are missing. If available, SCVs and their putative parental isolates should be genotyped to determine clonality. Since their detection has significant implications for the treatment of the infection, which is usually chronic and relapsing, SCV findings should be specifically reported, commented on, and managed in close collaboration with the microbiological laboratory and the involved clinicians. Full article
(This article belongs to the Special Issue A Themed Issue in Honor of Professor Richard Proctor—Outstanding Contributions in the Fields of Persistent Staphylococcus aureus Infections)
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21 pages, 1439 KiB  
Review
Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia: Host, Pathogen, and Treatment
by Joshua B. Parsons, Annette C. Westgeest, Brian P. Conlon and Vance G. Fowler, Jr.
Antibiotics 2023, 12(3), 455; https://doi.org/10.3390/antibiotics12030455 - 24 Feb 2023
Cited by 15 | Viewed by 6322
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a devastating pathogen responsible for a variety of life-threatening infections. A distinctive characteristic of this pathogen is its ability to persist in the bloodstream for several days despite seemingly appropriate antibiotics. Persistent MRSA bacteremia is common and is [...] Read more.
Methicillin-resistant Staphylococcus aureus (MRSA) is a devastating pathogen responsible for a variety of life-threatening infections. A distinctive characteristic of this pathogen is its ability to persist in the bloodstream for several days despite seemingly appropriate antibiotics. Persistent MRSA bacteremia is common and is associated with poor clinical outcomes. The etiology of persistent MRSA bacteremia is a result of the complex interplay between the host, the pathogen, and the antibiotic used to treat the infection. In this review, we explore the factors related to each component of the host–pathogen interaction and discuss the clinical relevance of each element. Next, we discuss the treatment options and diagnostic approaches for the management of persistent MRSA bacteremia. Full article
(This article belongs to the Special Issue A Themed Issue in Honor of Professor Richard Proctor—Outstanding Contributions in the Fields of Persistent Staphylococcus aureus Infections)
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14 pages, 1802 KiB  
Review
Subpopulations in Strains of Staphylococcus aureus Provide Antibiotic Tolerance
by Matipaishe Mashayamombe, Miguel Carda-Diéguez, Alex Mira, Robert Fitridge, Peter S. Zilm and Stephen P. Kidd
Antibiotics 2023, 12(2), 406; https://doi.org/10.3390/antibiotics12020406 - 17 Feb 2023
Cited by 4 | Viewed by 2482
Abstract
The ability of Staphylococcus aureus to colonise different niches across the human body is linked to an adaptable metabolic capability, as well as its ability to persist within specific tissues despite adverse conditions. In many cases, as S. aureus proliferates within an anatomical [...] Read more.
The ability of Staphylococcus aureus to colonise different niches across the human body is linked to an adaptable metabolic capability, as well as its ability to persist within specific tissues despite adverse conditions. In many cases, as S. aureus proliferates within an anatomical niche, there is an associated pathology. The immune response, together with medical interventions such as antibiotics, often removes the S. aureus cells that are causing this disease. However, a common issue in S. aureus infections is a relapse of disease. Within infected tissue, S. aureus exists as a population of cells, and it adopts a diversity of cell types. In evolutionary biology, the concept of “bet-hedging” has established that even in positive conditions, there are members that arise within a population that would be present as non-beneficial, but if those conditions change, these traits could allow survival. For S. aureus, some of these cells within an infection have a reduced fitness, are not rapidly proliferating or are the cause of an active host response and disease, but these do remain even after the disease seems to have been cleared. This is true for persistence against immune responses but also as a continual presence in spite of antibiotic treatment. We propose that the constant arousal of suboptimal populations at any timepoint is a key strategy for S. aureus long-term infection and survival. Thus, understanding the molecular basis for this feature could be instrumental to combat persistent infections. Full article
(This article belongs to the Special Issue A Themed Issue in Honor of Professor Richard Proctor—Outstanding Contributions in the Fields of Persistent Staphylococcus aureus Infections)
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