Biology subjects

Bayer, A.

Publications and source records attributed to Bayer, A..

6 recordsLinked to original sources

bioRxiv2025

Optimizing phage-antibiotic combinations: impact of administration order against daptomycin non-susceptible (DNS) MRSA clinical isolates

BackgroundThe rise of bacterial resistance has driven the exploration of novel therapies, such as bacteriophage-antibiotic cocktails (PACs), which have shown in vitro promise against resistant pathogens, including daptomycin non-susceptible (DNS-MRSA) strains. While daptomycin has been a cornerstone for treating MRSA bacteremia and vancomycin-refractory infective endocarditis, the emergence of DNS-MRSA presents a significant challenge due to high morbidity, mortality, and rapid intrinsic resistance development. MethodsPhages Intesti13 and Sb-1, were selected for their unique host ranges and activity against sixteen DNS-MRSA strains. Synergy with antibiotics was assessed via growth suppression curves and 24-hour time-kill assays (TKAs) across administration sequences and MIC increments. Selected regimens were further assessed in an ex-vivo simulated endocardial vegetation (SEV) models, with pharmacokinetic analyses confirming target antibiotic concentrations. ResultsIn the ex-vivo SEV model, simultaneous PAC administration using daptomycin{+/-}phage, showed superior bactericidal activity over sequential treatments in isolate C6 (p<0.01). Similarly, in the same model, C2 reached detection limits within 48h and remained suppressed for 120h (p<0.0037). Sequential outcomes varied by phage-antibiotic order and antibiotic choice. Simultaneous and phage-first regimens outperformed antibiotic-first, especially in 24h TKAs, but showed variability at lower MICs and between in-vitro and ex-vivo settings. ConclusionThis study highlights PACs potential for DNS-MRSA treatment, emphasizing the importance of administration timing. The observed differences across clinical strains emphasize the need for strain-specific evaluations and a deeper understanding of phage-antibiotic interactions to optimize therapy. Future research must focus on expanding phage diversity, refining protocols, and clinically validating sequential strategies to enhance PAC efficacy.

microbiology↗

bioRxiv2023

A single polymorphic residue in humans underlies species-specific restriction of HSV-1 by the antiviral protein MxB

Myxovirus resistance proteins (MxA and MxB) are interferon-induced proteins that exert antiviral activity against a diverse range of RNA and DNA viruses. In primates, MxA has been shown to inhibit myxoviruses, bunyaviruses, and hepatitis B virus, whereas MxB restricts retroviruses and herpesviruses. As a result of their conflicts with viruses, both genes have been undergoing diversifying selection during primate evolution. Here, we investigate how MxB evolution in primates has affected its restriction of herpesviruses. In contrast to human MxB, we find that most primate orthologs, including the closely related chimpanzee MxB, do not inhibit HSV-1 replication. However, all primate MxB orthologs tested restrict human cytomegalovirus. Through the generation of human and chimpanzee MxB chimeras we show that a single residue, M83, is the key determinant of restriction of HSV-1 replication. Humans are the only primate species known to encode a methionine at this position, whereas most other primate species encode a lysine. Residue 83 is also the most polymorphic residue in MxB in human populations, with M83 being the most common variant. However, [~]2.5% of human MxB alleles encode a threonine at this position, which does not restrict HSV-1. Thus, a single amino acid variant in MxB, which has recently risen to high frequency in humans, has endowed humans with HSV-1 antiviral activity. ImportanceHerpesviruses present a major global disease burden. Understanding the host cell mechanisms that block viral infections as well as how viruses can evolve to counteract these host defenses is critically important for understanding viral disease pathogenesis, and for developing therapeutic tools aimed at treating or preventing viral infections. Additionally, understanding how these host and viral mechanisms adapt to counter one another can aid in identifying the risks of, and barriers to, cross-species transmission events. As highlighted by the recent SARS-CoV-2 pandemic, episodic transmission events can have severe consequences for human health. This study reveals that the major human variant of the antiviral protein MxB inhibits the human pathogen HSV-1, whereas human minor variants and orthologous MxB genes from even closely related primates do not. Thus, in contrast to the many antagonistic virus-host interactions in which the virus is successful in thwarting the defense systems of their native hosts, in this case the human gene appears to be at least temporarily winning at this interface of the primate-herpesviral evolutionary arms race. Our findings further show that a polymorphism at amino acid 83 in a small fraction of the human population is sufficient to abrogate MxBs ability to inhibit HSV-1, which could have important implications for human susceptibility to HSV-1 pathogenesis.

microbiology↗

bioRxiv2021

Efficacy of Anti-Staphylococcal Lysin, LSVT-1701, in Combination with Daptomycin in Experimental Left-Sided Infective Endocarditis Due to Methicillin-Resistant Staphylococcus aureus (MRSA)

MRSA endovascular infections are frequently recalcitrant to treatment with standard-of-care antibiotics. Anti-staphylococcal phage lysins represent important candidate adjunctive agents against invasive MRSA infections because of both their microbicidal and anti-biofilm properties. We utilized the rabbit model of aortic valve infective endocarditis (using the prototype MRSA strain, MW2) to examine the combined efficacy of the lysin, LSVT-1701, plus daptomycin. LSVT-1701 was given at two dose-regimens (32.5 mg/kg and 50 mg/kg) with different dose-durations (single dose vs daily dose for 2 d vs daily dose for 4 d); daptomycin was given at a sub-lethal daily dose of 4 mg/kg for 4 d to maximize potential synergistic interaction outcomes. The combination of LSVT-1701 plus daptomycin was highly effective at reducing target tissue MRSA counts (cardiac vegetations, kidneys, and spleen), especially when the lysin was given for multiple days and/or at higher daily doses. Of importance, when given for four daily doses, both lysin dose-regimens in combination with daptomycin sterilized all target tissues. These findings suggest that LSVT-1701 warrants further clinical evaluation as adjunctive therapy for the treatment of invasive MRSA infections.

microbiology↗

bioRxiv2019

Ability of Bicarbonate Supplementation to Sensitize Selected Methicillin-Resistant Staphylococcus aureus (MRSA) Strains to β-Lactam Antibiotics in an Ex Vivo Simulated Endocardial Vegetation Model

Supplementation of standard growth media (cation-adjusted Mueller-Hinton Broth [CAMHB]) with bicarbonate (NaHCO3) significantly increases {beta}-lactam susceptibility of selected MRSA strains (\"NaHCO3-responsive\"). This \"sensitization\" phenomenon translated to enhanced {beta}-lactam efficacy in a rabbit model of endocarditis. The present study evaluated NaHCO3-mediated {beta}-lactam MRSA sensitization using an ex vivo pharmacodynamic model, featuring simulated endocardial vegetations (SEVs), to more closely mimic the host microenvironment. Four previously described MRSA strains were used: two each exhibiting in vitro \"NaHCO3-responsive\" or \"NaHCO3-nonresponsive\" phenotypes. Cefazolin (CFZ) and oxacillin (OXA) were evaluated in CAMHB{+/-}NaHCO3. Intra-SEV MRSA killing was determined over 72 hr exposure. In both NaHCO3-responsive strains, supplementation with 25 mM or 44 mM NaHCO3 significantly reduced {beta}-lactam MICs to below the OXA susceptibility breakpoint ([≤] 4 mg/L) resulting in bactericidal activity ([≥] 3 log kill) in the model for both OXA and CFZ. In contrast, neither in vitro-defined NaHCO3-nonresponsive MRSA strains showed significant sensitization in the SEV model to either {beta}-lactam. At both NaHCO3 concentrations, the fractional time-above-MIC was >50% for both CFZ and OXA in the NaHCO3-responsive MRSA. Also, in RPMI+10% LB media (proposed as a more host-mimicking microenvironment and containing 25 mM NaHCO3), both CFZ and OXA exhibited enhanced bactericidal activity against each NaHCO3-responsive strain in the SEV model. Neither CFZ nor OXA exposures selected for high-level {beta}-lactam-resistant mutants within SEVs. Thus, in this ex vivo model of endocarditis, in the presence of NaHCO3 supplementation, both CFZ and OXA are highly active against MRSA strains that demonstrate similar enhanced susceptibility in NaHCO3-supplemented media in vitro.

microbiology↗

bioRxiv2019

Pitfalls in estimating the global carbon removal via forest expansion - a comment on Bastin et al. (2019)

We believe the carbon removal potential of 205 Gt C reported by Bastin et al. (2019) to be overestimated. The authors did not consider the carbon already stored on the land with identified tree restoration potential. For instance, grasslands and degraded forests have similar soil carbon stocks as old-growth forests. Accounting for these inconsistencies in the calculation, we estimate a carbon removal potential of 81 Gt C, i.e. only 39% of the Bastin et al. estimate. In addition, some of the assumptions about potential restoration area seem questionable and an essential question remains unanswered: why do areas identified as suitable for tree growth currently lack tree cover?

ecology↗

bioRxiv2019

Bicarbonate Resensitization of Methicillin-Resistant Staphylococcus aureus to β-Lactam Antibiotics

Endovascular infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major healthcare concern, especially infective endocarditis (IE). Standard antimicrobial susceptibility testing (AST) defines most MRSA strains as resistant to {beta}-lactams, often leading to use of costly and/or toxic treatment regimens. In this investigation, five prototype MRSA strains, representing the range of genotypes in current clinical circulation, were studied. We identified two distinct MRSA phenotypes upon AST using standard media, with or without sodium bicarbonate (NaHCO3) supplementation: one highly susceptible to the anti-staphylococcal {beta}-lactams, oxacillin and cefazolin ( NaHCO3-responsive) and one resistant to such agents ( NaHCO3-nonresponsive). These phenotypes accurately predicted clearance profiles of MRSA from target tissues in experimental MRSA IE treated with each {beta}-lactam. Mechanistically, NaHCO3 reduced expression of two key genes involved in the MRSA phenotype, mecA and sarA, leading to decreased production of penicillin-binding protein (PBP) 2a (that mediates methicillin resistance), in NaHCO3-responsive (but not in NaHCO3-nonresponsive) strains. Moreover, both cefazolin and oxacillin synergistically killed NaHCO3-responsive strains in the presence of the host defense antimicrobial peptide (LL-37) in NaHCO3-supplemented media. These findings suggest that AST of MRSA strains in NaHCO3-containing media may potentially identify infections caused by NaHCO3-responsive strains that are appropriate for {beta}-lactam therapy.

microbiology↗