scholarly journals Structure-guided microbial targeting of antistaphylococcal prodrugs

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Justin J Miller ◽  
Ishaan T Shah ◽  
Jayda Hatten ◽  
Yasaman Barekatain ◽  
Elizabeth A Mueller ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cellular Uptake ◽  
Oral Absorption ◽  
Therapeutic Potential ◽  
Structural Basis ◽  
Substrate Specificities ◽  
Ester Substrate ◽  
Human And Mouse ◽  
Ester Prodrugs ◽  
Microbial Esterase

Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs in Staphylococcus aureus. Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Finally, we establish the carboxy ester substrate specificities of human and mouse sera, ultimately identifying several promoieties likely to be serum esterase-resistant and microbially labile. These studies will enable structure-guided design of anti-staphylococcal promoieties and expand the range of molecules to target staphylococcal pathogens.

scholarly journals Structure-guided microbial targeting of antistaphylococcal prodrugs

2020 ◽  
Author(s):  
Justin Miller ◽  
Ishaan T Shah ◽  
Jayda Hatten ◽  
Yasaman Barekatain ◽  
Elizabeth A Mueller ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Oral Absorption ◽  
Structural Basis ◽  
Target Delivery ◽  
Prodrug Activation ◽  
Substrate Specificities ◽  
Ester Prodrug ◽  
Ester Substrate ◽  
Human And Mouse ◽  
Ester Prodrugs

Carboxy ester prodrugs have been widely employed as a means to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can successfully mask problematic chemical features that prevent cellular uptake and can be used to target delivery of compounds to specific tissues. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, curbing their potential therapeutic applications. While carboxy ester-based prodrug targeting is feasible, it has been limited in microbes due to a paucity of information about the selectivity of microbial esterases. Here we identify the bacterial esterases, GloB and FrmB, that are required for carboxy ester prodrug activation in Staphylococcus aureus. Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Finally, we establish the carboxy ester substrate specificities of human and mouse sera, identifying several promoieties likely to be serum esterase-resistant while still being microbially labile. These studies lay the groundwork for structure guided design of antistaphyloccal promoieties, enabling a massive expansion of the antistaphyloccal druggable space.

scholarly journals Structural basis of inhibition of a transporter from Staphylococcus aureus, NorC, through a single-domain camelid antibody

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sushant Kumar ◽  
Arunabh Athreya ◽  
Ashutosh Gulati ◽  
Rahul Mony Nair ◽  
Ithayaraja Mahendran ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Pathogenic Bacteria ◽  
Major Facilitator Superfamily ◽  
Single Domain ◽  
Fluoroquinolone Resistance ◽  
Structural Basis ◽  
Antibody Complex ◽  
Complementarity Determining Regions ◽  
Major Facilitator ◽  
Alternating Access

AbstractTransporters play vital roles in acquiring antimicrobial resistance among pathogenic bacteria. In this study, we report the X-ray structure of NorC, a 14-transmembrane major facilitator superfamily member that is implicated in fluoroquinolone resistance in drug-resistant Staphylococcus aureus strains, at a resolution of 3.6 Å. The NorC structure was determined in complex with a single-domain camelid antibody that interacts at the extracellular face of the transporter and stabilizes it in an outward-open conformation. The complementarity determining regions of the antibody enter and block solvent access to the interior of the vestibule, thereby inhibiting alternating-access. NorC specifically interacts with an organic cation, tetraphenylphosphonium, although it does not demonstrate an ability to transport it. The interaction is compromised in the presence of NorC-antibody complex, consequently establishing a strategy to detect and block NorC and related transporters through the use of single-domain camelid antibodies.

scholarly journals Dietary Curcumin: Correlation between Bioavailability and Health Potential

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2147 ◽  
Author(s):  
Michele Dei Cas ◽  
Riccardo Ghidoni
Keyword(s):  
Small Intestine ◽  
Cellular Uptake ◽  
Oral Delivery ◽  
Therapeutic Potential ◽  
Pharmacokinetic Profile ◽  
Yellow Pigment ◽  
The Body ◽  
Anti Cancer ◽  
Poor Absorption ◽  
Oral Delivery Systems

The yellow pigment curcumin, extracted from turmeric, is a renowned polyphenol with a broad spectrum of health properties such as antioxidant, anti-inflammatory, anti-cancer, antidiabetic, hepatoprotective, anti-allergic, anti-dermatophyte, and neuroprotective. However, these properties are followed by a poor pharmacokinetic profile which compromises its therapeutic potential. The association of low absorption by the small intestine and the extensive reductive and conjugative metabolism in the liver dramatically weakens the oral bioavailability. Several strategies such as inhibition of curcumin metabolism with adjuvants as well as novel solid and liquid oral delivery systems have been tried to counteract curcumin poor absorption and rapid elimination from the body. Some of these drug deliveries can successfully enhance the solubility, extending the residence in plasma, improving the pharmacokinetic profile and the cellular uptake.

scholarly journals Structural Basis for Linezolid Binding Site Rearrangement in the Staphylococcus aureus Ribosome

mBio ◽  
2017 ◽  
Vol 8 (3) ◽  
Author(s):  
Matthew J. Belousoff ◽  
Zohar Eyal ◽  
Mazdak Radjainia ◽  
Tofayel Ahmed ◽  
Rebecca S. Bamert ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Structural Information ◽  
Structural Basis ◽  
Common Mechanism ◽  
Resistance Mutations ◽  
Antimicrobial Drugs ◽  
Linezolid Resistance ◽  
Drug Modification ◽  
Antibiotic Resistance Mutations ◽  
Shed Light

ABSTRACT An unorthodox, surprising mechanism of resistance to the antibiotic linezolid was revealed by cryo-electron microscopy (cryo-EM) in the 70S ribosomes from a clinical isolate of Staphylococcus aureus. This high-resolution structural information demonstrated that a single amino acid deletion in ribosomal protein uL3 confers linezolid resistance despite being located 24 Å away from the linezolid binding pocket in the peptidyl-transferase center. The mutation induces a cascade of allosteric structural rearrangements of the rRNA that ultimately results in the alteration of the antibiotic binding site. IMPORTANCE The growing burden on human health caused by various antibiotic resistance mutations now includes prevalent Staphylococcus aureus resistance to last-line antimicrobial drugs such as linezolid and daptomycin. Structure-informed drug modification represents a frontier with respect to designing advanced clinical therapies, but success in this strategy requires rapid, facile means to shed light on the structural basis for drug resistance (D. Brown, Nat Rev Drug Discov 14:821–832, 2015, https://doi.org/10.1038/nrd4675 ). Here, detailed structural information demonstrates that a common mechanism is at play in linezolid resistance and provides a step toward the redesign of oxazolidinone antibiotics, a strategy that could thwart known mechanisms of linezolid resistance. IMPORTANCE The growing burden on human health caused by various antibiotic resistance mutations now includes prevalent Staphylococcus aureus resistance to last-line antimicrobial drugs such as linezolid and daptomycin. Structure-informed drug modification represents a frontier with respect to designing advanced clinical therapies, but success in this strategy requires rapid, facile means to shed light on the structural basis for drug resistance (D. Brown, Nat Rev Drug Discov 14:821–832, 2015, https://doi.org/10.1038/nrd4675 ). Here, detailed structural information demonstrates that a common mechanism is at play in linezolid resistance and provides a step toward the redesign of oxazolidinone antibiotics, a strategy that could thwart known mechanisms of linezolid resistance.

Therapeutic Potential of Green Synthesized Metallic Nanoparticles against Staphylococcus aureus

2021 ◽  
Vol 13 ◽  
Author(s):  
Meron Moges Tsegaye ◽  
Garima Chouhan ◽  
Molla Fentie ◽  
Priya Tyagi ◽  
Parma Nand
Keyword(s):  
Staphylococcus Aureus ◽  
Metallic Nanoparticles ◽  
Therapeutic Potential ◽  
Multidrug Resistant ◽  
Health Condition ◽  
World Health ◽  
Therapeutic Modality ◽  
Effective Control ◽  
Bacterial Strains ◽  
Synthesis Of Nanoparticles

Background: The recent treatment challenges posed by the widespread emergence of pathogenic Multidrug‐Resistant (MDR) bacterial strains are a cause of huge health troubles worldwide. Infections caused by MDR organisms are associated with longer period of hospitalization, increased mortality, and inflated healthcare costs. Staphylococcus aureus is one of these MDR organisms identified as an urgent threat to human health by the World Health Organization. Infections caused by S. aureus may range from simple cutaneous infestations to life threatening bacteremia. S. aureus infections get easily escalated in severely ill, hospitalized and or immunocompromised patients with incapacitated immune system. Also, in HIV-positive patients S. aureus ranks amongst one of the most common comorbidities where it can further worsen a patient’s health condition. At present anti-staphylococcal therapy is reliant typically on chemotherapeutics that are gathering resistance and pose unfavorable side-effects. Thus, newer drugs are required that can bridge these shortcomings and aid effective control against S. aureus. Objective: In this review, we summarize drug resistance exhibited by S. aureus and lacunae in current anti-staphylococcal therapy, nanoparticles as an alternative therapeutic modality. The focus lays on various green synthesized nanoparticles, their mode of action and application as potent antibacterial compounds against S. aureus. Conclusion: Use of nanoparticles as anti-bacterial drugs has gained momentum in recent past and green synthesized nanoparticles, which involves microorganisms and plants or their byproducts for synthesis of nanoparticles offer a potent, as well as environment friendly solution in warfare against MDR bacte.

Abstract 1696: Compound RVX-208 Modulates HDL-C Levels and Function in Non-human Primates and in Early (phase I) Human Trials

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Larbi Krimbou ◽  
Ravi Jahagirdar ◽  
Dana Bailey ◽  
Anouar Hafiane ◽  
Isabelle Ruel ◽  
...  
Keyword(s):  
Oral Administration ◽  
Healthy Volunteers ◽  
Size Distribution ◽  
Cholesterol Efflux ◽  
Oral Absorption ◽  
Therapeutic Potential ◽  
Human Study ◽  
Treated Group ◽  
Atherosclerotic Cardiovascular Disease ◽  
Hdl Function

The novel compound RVX-208 is a small molecule that upregulates the gene expression of apoA-I and raises HDL-C in non-human primates. Here, we examined the effects of oral administration of RVX-208 on serum apoA-I and HDL-C levels , HDL size distribution, and HDL function. African green monkeys received RVX-208 (7.5, 15 and 30 mg/kg; twice daily and 60 mg/kg; once daily) or vehicle control for 28, 42, and 63 days. We report that RVX-208 chronic treatment resulted in a highly significant increase in the average of serum apoA-I and HDL-C levels (57% and 92%, respectively). Interestingly, RVX-208 treatment modified the distribution of HDL particle size causing a significant increase in preβ1-LpA-I and larger α1-LpA-I species. The ability of serum to promote cholesterol efflux via ABCA1, ABCG1 or SR-BI-dependent pathways in a cell culture model was significantly increased by RVX-208. The phase Ia safety and pharmacokinetic human study comprised of a total of 80 subjects. In the multiple ascending dose arm, 24 participants were randomly assigned to 3 cohorts of 8 healthy volunteers (6 active and 2 placebo), and received oral administration of RVX-208 at 2, 3 and 8 mg/kg per day or placebo for 7 days. The compound was well tolerated and had good oral absorption meeting the objectives of safety and pharmacokinetics. ApoA-I, HDL-C, HDL size distribution and ABCA1-dependent cholesterol efflux were assessed at days 1 (predose) and 7. The percent change from baseline to day 7 for apoA-I was 11% higher (P = 0.03) in the RVX-208 treated participants compared to placebo. Interestingly, preβ1-LpA-I change was 30% (P = 0.02) higher in the actively treated group and was found to strongly correlate with increased apoA-I levels (R2 = 0.72). Furthermore, ABCA1-dependent cholesterol efflux change was 10% higher (P = 0.03) and was found to correlate with increased preβ1-LpA-I . Taken together, these pharmacodynamic data from human healthy volunteers show consistent trends in apoA-I production and HDL functionality, supporting the findings in the African green monkey. Further investigation of the effect of RVX-208 on the HDL metabolic pathway is ongoing in humans and animals to establish the mechanisms of action and therapeutic potential in treating atherosclerotic cardiovascular disease.

scholarly journals Making the Most of the Host; Targeting the Autophagy Pathway Facilitates Staphylococcus aureus Intracellular Survival in Neutrophils

2021 ◽  
Vol 12 ◽  
Author(s):  
Emilio G. Vozza ◽  
Michelle E. Mulcahy ◽  
Rachel M. McLoughlin
Keyword(s):  
Staphylococcus Aureus ◽  
Therapeutic Potential ◽  
Systemic Infection ◽  
Opportunistic Pathogen ◽  
Intracellular Survival ◽  
Innate Immune ◽  
Pathogenic Role ◽  
New Host ◽  
Increased Risk ◽  
Autophagy Pathway

The success of Staphylococcus aureus as a human commensal and an opportunistic pathogen relies on its ability to adapt to several niches within the host. The innate immune response plays a key role in protecting the host against S. aureus infection; however, S. aureus adeptness at evading the innate immune system is indisputably evident. The “Trojan horse” theory has been postulated to describe a mechanism by which S. aureus takes advantage of phagocytes as a survival niche within the host to facilitate dissemination of S. aureus to secondary sites during systemic infection. Several studies have determined that S. aureus can parasitize both professional and non-professional phagocytes by manipulating the host autophagy pathway in order to create an intracellular survival niche. Neutrophils represent a critical cell type in S. aureus infection as demonstrated by the increased risk of infection among patients with congenital neutrophil disorders. However, S. aureus has been repeatedly shown to survive intracellularly within neutrophils with evidence now supporting a pathogenic role of host autophagy. By manipulating this pathway, S. aureus can also alter the apoptotic fate of the neutrophil and potentially skew other important signalling pathways for its own gain. Understanding these critical host-pathogen interactions could lead to the development of new host directed therapeutics for the treatment of S. aureus infection by removing its intracellular niche and restoring host bactericidal functions. This review discusses the current findings surrounding intracellular survival of S. aureus within neutrophils, the pathogenic role autophagy plays in this process and considers the therapeutic potential for targeting this immune evasion mechanism.

scholarly journals Chrysin-Loaded Chitosan Nanoparticles Potentiates Antibiofilm Activity against Staphylococcus aureus

Pathogens ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 115 ◽  
Author(s):  
Busi Siddhardha ◽  
Uday Pandey ◽  
K. Kaviyarasu ◽  
Rajasekharreddy Pala ◽  
Asad Syed ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Therapeutic Potential ◽  
Chitosan Nanoparticles ◽  
Cell Surface Hydrophobicity ◽  
Surface Hydrophobicity ◽  
Inhibitory Effect ◽  
Biological Properties ◽  
Antibiofilm Activity ◽  
Growth Curve Analysis ◽  
Biofilm Development

The application of nanotechnology in medicine is gaining popularity due to its ability to increase the bioavailability and biosorption of numerous drugs. Chrysin, a flavone constituent of Orocylumineicum vent is well-reported for its biological properties. However, its therapeutic potential has not been fully exploited due to its poor solubility and bioavailability. In the present study, chrysin was encapsulated into chitosan nanoparticles using TPP as a linker. The nanoparticles were characterized and investigated for their anti-biofilm activity against Staphylococcus aureus. At sub-Minimum Inhibitory Concentration, the nanoparticles exhibited enhanced anti-biofilm efficacy against S. aureus as compared to its bulk counterparts, chrysin and chitosan. The decrease in the cell surface hydrophobicity and exopolysaccharide production indicated the inhibitory effect of the nanoparticles on the initial stages of biofilm development. The growth curve analysis revealed that at a sub-MIC, the nanoparticles did not exert a bactericidal effect against S. aureus. The findings indicated the anti-biofilm activity of the chrysin-loaded chitosan nanoparticles and their potential application in combating infections associated with S. aureus.

Amelioration of sperm immobilisation factor-induced infertility by bacterial antigenic determinants cross-reacting with spermatozoa

2019 ◽  
Vol 31 (3) ◽  
pp. 602 ◽  
Author(s):  
Deepali Thaper ◽  
Deepak K. Rahi ◽  
Vijay Prabha
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Molecular Mimicry ◽  
Fluorescein Isothiocyanate ◽  
Antigenic Determinants ◽  
Sperm Function ◽  
Contraceptive Effect ◽  
Normal Sperm ◽  
Ameliorative Effect ◽  
Human And Mouse

A strain of Staphylococcus aureus, capable of invitro immobilisation of human and mouse spermatozoa, was already present in our laboratory. Therefore, in the present study, the factor responsible (sperm immobilisation factor, SIF) was isolated and purified. It was found to compromise not only motility, but also viability, morphology and Mg2+-ATPase activity of mouse spermatozoa. Also, SIF (250μgmL−1), when administered intravaginally in female BALB/c mice before mating, showed 100% contraceptive effect. Moreover, fluorescein isothiocyanate-labelled SIF was also found to bind mouse spermatozoa and various motile as well as non-motile bacteria, indicating the presence of common SIF-binding receptors on spermatozoa and bacteria. Further, to demonstrate molecular mimicry, the amelioration of SIF-induced impairment of sperm function by a SIF-binding bacterial receptor was compelling. For this, the SIF-binding receptor from Escherichia coli (E-SBR) was purified and evaluated for its ameliorative effect on SIF-induced sperm impairment invitro and invivo. Interestingly, upon the addition of mouse spermatozoa to SIF pre-incubated with E-SBR, an ameliorative effect against SIF-induced impairment of sperm function could be observed through analysis of normal sperm parameters (motility, viability, morphology, Mg2+-dependent ATPase levels). E-SBR also blocked binding of labelled SIF to spermatozoa and bacteria and alleviated SIF-induced infertility in female BALB/c mice. This provided evidence for molecular similarities between bacteria and spermatozoa, owing to which anti-bacterial antibodies cross-reacting with spermatozoa might be produced and infertility might follow.

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