Biology subjects

Jusuf, S.

Publications and source records attributed to Jusuf, S..

5 recordsLinked to original sources

bioRxiv2022

Fingerprint SRS Imaging Unveils Ergosteryl Ester as a Metabolic Signature of Azole-Resistant Candida albicans

Candida albicans (C. albicans), a major fungal pathogen, causes life-threatening infections in immunocompromised individuals. Fluconazole (FLC) is recommended as first-line therapy for treatment of invasive fungal infections. Yet, the widespread use of FLC has resulted in increased antifungal resistance among different strains of Candida, especially C. albicans, which is a leading source of hospital-acquired infections. Here, by hyperspectral stimulated Raman scattering (hSRS) imaging of single fungal cells in the fingerprint window and pixel-wise spectral unmixing, we report aberrant ergosteryl ester accumulation in azole-resistant C. albicans compared to azole-susceptible species. This accumulation was a consequence of de novo lipogenesis. Lipid profiling by mass spectroscopy identified ergosterol oleate to be the major species stored in azole-resistant C. albicans. Blocking ergosterol esterification by oleate and suppressing sterol synthesis by FLC synergistically suppressed the viability of C. albicans in vitro and limited the growth of biofilm on mouse skin in vivo. Our findings highlight a metabolic marker and a new therapeutic strategy for targeting azole-resistant C. albicans by interrupting the esterified ergosterol biosynthetic pathway. Significance StatementInvasive fungal infections and increasing antifungal resistance are emerging threats to public health with high morbidity and mortality. Despite the advances in azole resistance mechanisms, it remains unclear why some fungal species are intrinsically resistant to or easily acquire resistance to multiple antifungal drugs. Here, using fingerprint SRS microscopy, we uncovered a molecular signature, aberrant ergosteryl ester accumulation, linked to the azole resistance of Candida species. An antifungal treatment strategy combining oleate (inhibitor of ersgosteryl esterification) and azole significantly attenuates the azole resistance and the viability of C. albicans in vitro and in vivo. Our work opens a new way to detect and treat azole-resistant fungal infections by targeting ergosterol metabolism.

microbiology↗

bioRxiv2021

Photoinactivation of catalase sensitizes Candida albicans and Candida auris to ROS-producing agents and immune cells

Nearly all organisms found in nature have evolved and developed their own specific strategies to cope with reactive oxygen species (ROS). Catalase, a heme-containing tetramer protein expressed in a broad range of aerobic fungi, has been utilized as an essential enzymatic ROS detoxifying mechanism, and shows remarkable efficiency in degrading hydrogen peroxide (H2O2) for fungal cell survival and host invasion. Here, we demonstrate that catalase inactivation with blue light renders fungal cells highly susceptible to ROS attack, thus resembling a strength-to-weakness optical switch. To unveil catalase as the underlying molecular target of blue light and its inactivation mechanism, we systematically compared wild-type Candida albicans to a catalase-deficient mutant strain for susceptibility to ROS in the absence/presence of 410 nm treatment. Upon testing on a wide range of fungal species and strains, we found that intracellular catalase could be effectively and universally inactivated by 410 nm blue light. We find that the photoinactivation of catalase in combination with ROS-generating agents is highly effective and potent in achieving full eradication of multiple fungal species and strains, including multiple clinical strains of Candida auris, the causative agent of the global fungal epidemic. In addition, photoinactivation of catalase is shown to facilitate macrophage killing of intracellular Candida albicans. The antifungal efficacy of catalase photoinactivation is further validated using a Candida albicans-induced mouse model of skin abrasion. Taken together, our findings offer a novel catalase-photoinactivation approach to address multidrug-resistant Candida infections.

microbiology↗

bioRxiv2021

Photoinactivation of Catalase Sensitizes Wide-Ranging Bacteria to ROS-Producing Agents and Immune Cells

Bacteria have evolved to cope with the detrimental effects of reactive oxygen species (ROS) using their essential molecular components. Catalase, a heme-containing tetramer protein expressed universally in most of the aerobic bacteria, plays an indispensable role in scavenging excess hydrogen peroxide (H2O2). Here, through utilization of wild-type and catalase-deficient mutants, we identified catalase as an endogenous therapeutic target of 400-420 nm blue light. Catalase residing in bacteria could be effectively inactivated by blue light, subsequently rendering the pathogens extremely vulnerable to H2O2 and H2O2-producing agents. As a result, photoinactivation of catalase and H2O2 synergistically eliminate a wide range of catalase-positive planktonic bacteria and P. aeruginosa inside biofilms. In addition, photoinactivation of catalase is shown to facilitate macrophages to defend against intracellular pathogens. The antimicrobial efficacy of catalase photoinactivation is further validated using a Pseudomonas aeruginosa-induced mice abrasion model. Taken together, our findings offer a catalase-targeting phototherapy against multidrug-resistant bacterial infections.

microbiology↗

bioRxiv2020

Granadaene Photobleaching Reduces the Virulence and Increases Antimicrobial Susceptibility of Streptococcus agalactiae

Streptococcus agalactiae, also known as Group B Streptococcus (GBS), is increasingly recognized as a major cause of soft tissue and invasive diseases in the elderly and diabetic populations. Antibiotics like penicillin are used with great frequency to treat these infections, although antimicrobial resistance is increasing among GBS strains and underlines a need for alternative methods not reliant on traditional antibiotics. GBS hemolysin/cytolysin and granadaene pigment are two major linked virulence factors that contribute to GBS pathogenicity. Here we show that photobleaching of the antioxidant granadaene renders the pathogen more susceptible to killing by mouse macrophages and to hydrogen peroxide killing. Photo-treatment also leads to loss of activity of the linked hemolysin/cytolysin although photobleaching disproportionally affected the activity of the two factors. Treatment with light also affected GBS membrane permeability and contribute to increased susceptibility to the cell membrane active antibiotic daptomycin and to penicillin. Overall our study demonstrates a dual effect of photobleaching on the virulence and antimicrobial susceptibility of GBS and suggests a novel approach for the treatment of GBS infection. Our findings further provide new insight on the relationship between GBS hemolysin and the granadaene pigment. ImportanceFor elderly individuals or those with chronic underlying conditions (such as diabetes), skin infections caused by Streptococcus agalactiae represent a significant risk for the development of invasive disease. S. agalactiae strains are becoming increasingly resistant to antibiotics. By utilizing blue light to neutralize the granadaene pigment present in S. agalactiae, this paper presents a non-invasive and non-antibiotic reliant process capable of reducing GBS virulence while increasing the antimicrobial susceptibility of the bacterium. The differential effect of blue light on the linked GBS hemolysin/cytolysin and granadene pigment further provides new insight on the relationship between the two virulence factors. Overall photo-treatment represents a novel strategy for the treatment of S. agalactiae infections.

microbiology↗

bioRxiv2019

Photo-Disassembly of Membrane Microdomains Revives Conventional Antibiotics against MRSA

Confronted with the rapid evolution and dissemination of antibiotic resistance, there is an urgent need to develop alternative treatment strategies for drug-resistant pathogens. Here, we present an unconventional approach to restore the susceptibility of methicillin-resistant S. aureus (MRSA) to a broad spectrum of conventional antibiotics via photo-disassembly of functional membrane microdomains. The photo-disassembly of microdomains is based on effective photolysis of staphyloxanthin, the golden carotenoid pigment that gives its name. Upon pulsed laser treatment, cell membranes are found severely disorganized and malfunctioned to defense antibiotics, as unveiled by membrane permeabilization, membrane fluidification, and detachment of membrane protein, PBP2a. Consequently, our photolysis approach increases susceptibility and inhibits development of resistance to a broad spectrum of antibiotics including penicillins, quinolones, tetracyclines, aminoglycosides, lipopeptides, and oxazolidinones.\n\nOne Sentence SummaryUsing photons to crash S. aureus cell membrane and its formidable defense against a broad spectrum of antibiotics.

microbiology↗