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Microbiology and Molecular Biology... Jun 2023Clinical management of Staphylococcus aureus infections presents a challenge due to the high incidence, considerable virulence, and emergence of drug resistance... (Review)
Review
Clinical management of Staphylococcus aureus infections presents a challenge due to the high incidence, considerable virulence, and emergence of drug resistance mechanisms. The treatment of drug-resistant strains, such as methicillin-resistant S. aureus (MRSA), is further complicated by the development of tolerance and persistence to antimicrobial agents in clinical use. To address these challenges, membrane disruptors, that are not generally considered during drug discovery for agents against S. aureus, should be explored. The cell membrane protects S. aureus from external stresses and antimicrobial agents, but membrane-targeting antimicrobial agents are probably less likely to promote bacterial resistance. Nontypical linear cationic antimicrobial peptides (AMPs), highly modified AMPs such as daptomycin (lipopeptide), bacitracin (cyclic peptide), and gramicidin S (cyclic peptide), are currently in clinical use. Recent studies have demonstrated that AMPs and small molecules can penetrate the cell membrane of S. aureus, inhibit phospholipid biosynthesis, or block the passage of solutes between the periplasm and the exterior of the cell. In addition to their primary mechanism of action (MOA) that targets the bacterial membrane, AMPs and small molecules may also impact bacteria through secondary mechanisms such as targeting the biofilm, and downregulating virulence genes of S. aureus. In this review, we discuss the current state of research into cell membrane-targeting AMPs and small molecules and their potential mechanisms of action against drug-resistant physiological forms of S. aureus, including persister cells and biofilms.
Topics: Humans; Staphylococcus aureus; Anti-Bacterial Agents; Methicillin-Resistant Staphylococcus aureus; Antimicrobial Peptides; Anti-Infective Agents; Peptides, Cyclic; Cell Membrane; Biofilms; Staphylococcal Infections
PubMed: 37129495
DOI: 10.1128/mmbr.00037-22 -
Microbiology (Reading, England) Aug 2023In Gram-positive bacteria such as and the coagulase-negative staphylococci (CoNS), the accessory gene regulator () is a highly conserved but polymorphic quorum-sensing... (Review)
Review
In Gram-positive bacteria such as and the coagulase-negative staphylococci (CoNS), the accessory gene regulator () is a highly conserved but polymorphic quorum-sensing system involved in colonization, virulence and biofilm development. Signalling via depends on the interaction of an autoinducing peptide (AIP) with AgrC, a transmembrane sensor kinase that, once phosphorylated activates the response regulator AgrA. This in turn autoinduces AIP biosynthesis and drives target gene expression directly via AgrA or via the post-transcriptional regulator, RNAIII. In this review we describe the molecular mechanisms underlying the -mediated generation of, and response to, AIPs and the molecular basis of AIP-dependent activation and inhibition of AgrC. How the environment impacts on functionality is considered and the consequences of dysfunction for infection explored. We also discuss the concept of AIP-driven competitive interference between and the CoNS and its anti-infective potential.
Topics: Staphylococcus; Staphylococcus aureus; Peptides, Cyclic; Protein Kinases; Peptides; Quorum Sensing; Bacterial Proteins
PubMed: 37578829
DOI: 10.1099/mic.0.001381 -
International Journal of Molecular... Dec 2023stands as one of the most pervasive pathogens given its morbidity and mortality worldwide due to its roles as an infectious agent that causes a wide variety of diseases... (Review)
Review
stands as one of the most pervasive pathogens given its morbidity and mortality worldwide due to its roles as an infectious agent that causes a wide variety of diseases ranging from moderately severe skin infections to fatal pneumonia and sepsis. produces a variety of exotoxins that serve as important virulence factors in -related infectious diseases and food poisoning in both humans and animals. For example, staphylococcal enterotoxins (SEs) produced by induce staphylococcal foodborne poisoning; toxic shock syndrome toxin-1 (TSST-1), as a typical superantigen, induces toxic shock syndrome; hemolysins induce cell damage in erythrocytes and leukocytes; and exfoliative toxin induces staphylococcal skin scalded syndrome. Recently, Panton-Valentine leucocidin, a cytotoxin produced by community-associated methicillin-resistant (CA-MRSA), has been reported, and new types of SEs and staphylococcal enterotoxin-like toxins (SEls) were discovered and reported successively. This review addresses the progress of and novel insights into the molecular structure, biological activities, and pathogenicity of both the classic and the newly identified exotoxins produced by .
Topics: Animals; Humans; Staphylococcus aureus; Virulence; Methicillin-Resistant Staphylococcus aureus; Exotoxins; Staphylococcal Infections
PubMed: 38203566
DOI: 10.3390/ijms25010395 -
Deutsches Arzteblatt International Jun 2023
Topics: Humans; Methicillin-Resistant Staphylococcus aureus
PubMed: 37594462
DOI: 10.3238/arztebl.m2023.0131 -
Nature Microbiology Nov 2023Drug combinations can expand options for antibacterial therapies but have not been systematically tested in Gram-positive species. We profiled ~8,000 combinations of 65...
Drug combinations can expand options for antibacterial therapies but have not been systematically tested in Gram-positive species. We profiled ~8,000 combinations of 65 antibacterial drugs against the model species Bacillus subtilis and two prominent pathogens, Staphylococcus aureus and Streptococcus pneumoniae. Thereby, we recapitulated previously known drug interactions, but also identified ten times more novel interactions in the pathogen S. aureus, including 150 synergies. We showed that two synergies were equally effective against multidrug-resistant S. aureus clinical isolates in vitro and in vivo. Interactions were largely species-specific and synergies were distinct from those of Gram-negative species, owing to cell surface and drug uptake differences. We also tested 2,728 combinations of 44 commonly prescribed non-antibiotic drugs with 62 drugs with antibacterial activity against S. aureus and identified numerous antagonisms that might compromise the efficacy of antimicrobial therapies. We identified even more synergies and showed that the anti-aggregant ticagrelor synergized with cationic antibiotics by modifying the surface charge of S. aureus. All data can be browsed in an interactive interface ( https://apps.embl.de/combact/ ).
Topics: Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; Anti-Bacterial Agents; Gram-Positive Bacteria; Drug Combinations
PubMed: 37770760
DOI: 10.1038/s41564-023-01486-9 -
The Journal of Antibiotics Oct 2023Currently, antibiotic-resistant bacteria represent a serious threat to public health worldwide. Biofilm formation potentiates both virulence and antibiotic resistance of...
Currently, antibiotic-resistant bacteria represent a serious threat to public health worldwide. Biofilm formation potentiates both virulence and antibiotic resistance of bacteria. Therefore, the discovery of new antibacterial and antibiofilm compounds is an issue of paramount importance to combat and prevent hard-to-treat bacterial infections. Zeolitic-imidazolate-frameworks (ZIFs) are metallo-organic compounds known to have various interesting chemical and biological applications, including antibacterial properties. In this study, we synthesized ZIF-67 nanoparticles, formed by imidazolate anions and cobalt cations, and found that they inhibit the growth of Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus. Sub-inhibitory concentrations of ZIF-67 were also able to significantly reduce the biomass of pre-established biofilms of these pathogenic bacteria. On the other hand, the ZIF-67 nanoparticles had null or low cytotoxicity in mammalian cells at those concentrations showing antibacterial or antibiofilm activities. Thus, our results reveal the potential of ZIF-67 nanoparticles to be used against pathogenic bacteria.
Topics: Animals; Microbial Sensitivity Tests; Anti-Bacterial Agents; Staphylococcus aureus; Bacteria; Biofilms; Mammals
PubMed: 37337088
DOI: 10.1038/s41429-023-00637-8 -
International Journal of Molecular... Jul 2023sp. are the most commonly associated pathogens in infective endocarditis, especially within high-income nations. This along with the increasing burden of healthcare,... (Review)
Review
sp. are the most commonly associated pathogens in infective endocarditis, especially within high-income nations. This along with the increasing burden of healthcare, aging populations, and the protracted infection courses, contribute to a significant challenge for healthcare systems. A systematic review was conducted using relevant search criteria from PubMed, Ovid's version of MEDLINE, and EMBASE, and data were tabulated from randomized controlled trials (RCT), observational cohort studies, meta-analysis, and basic research articles. The review was registered with the OSF register of systematic reviews and followed the PRISMA reporting guidelines. Thirty-five studies met the inclusion criteria and were included in the final systematic review. The role of and its interaction with the protective shield and host protection functions was identified and highlighted in several studies. The interaction between infective endocarditis pathogens, vascular endothelium, and blood constituents was also explored, giving rise to the potential use of antiplatelets as preventative and/or curative agents. Several factors allow infections to proliferate within the host with numerous promoting and perpetuating agents. The complex interaction with the hosts' innate immunity also potentiates its virulence. The goal of this study is to attain a better understanding on the molecular pathways involved in infective endocarditis supported by and whether therapeutic avenues for the prevention and treatment of IE can be obtained. The use of antibiotic-treated allogeneic tissues have marked antibacterial action, thereby becoming the ideal substitute in native and prosthetic valvular infections. However, the development of effective vaccines against still requires in-depth studies.
Topics: Humans; Anti-Bacterial Agents; Endocarditis; Endocarditis, Bacterial; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus
PubMed: 37446247
DOI: 10.3390/ijms241311068 -
Nature Communications Nov 2023Multidrug-resistant (MDR) bacteria cause severe clinical infections and a high mortality rate of over 40% in patients with immunodeficiencies. Therefore, more effective,...
Multidrug-resistant (MDR) bacteria cause severe clinical infections and a high mortality rate of over 40% in patients with immunodeficiencies. Therefore, more effective, broad-spectrum, and accurate treatment for severe cases of infection is urgently needed. Here, we present an adoptive transfer of macrophages loaded with a near-infrared photosensitizer (Lyso700D) in lysosomes to boost innate immunity and capture and eliminate bacteria through a photodynamic effect. In this design, the macrophages can track and capture bacteria into the lysosomes through innate immunity, thereby delivering the photosensitizer to the bacteria within a single lysosome, maximizing the photodynamic effect and minimizing the side effects. Our results demonstrate that this therapeutic strategy eliminated MDR Staphylococcus aureus (MRSA) and Acinetobacter baumannii (AB) efficiently and cured infected mice in both two models with 100% survival compared to 10% in the control groups. Promisingly, in a rat model of central nervous system bacterial infection, we performed the therapy using bone marrow-divided macrophages and implanted glass fiber to conduct light irradiation through the lumbar cistern. 100% of infected rats survived while none of the control group survived. Our work proposes an efaficient and safe strategy to cure MDR bacterial infections, which may benefit the future clinical treatment of infection.
Topics: Humans; Rats; Mice; Animals; Photosensitizing Agents; Photochemotherapy; Staphylococcal Infections; Staphylococcus aureus; Bacteria; Macrophages; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Methicillin-Resistant Staphylococcus aureus; Acinetobacter baumannii
PubMed: 37945555
DOI: 10.1038/s41467-023-43074-9 -
Frontiers in Cellular and Infection... 2023Bacterial keratitis (bacterial infection of the cornea) is a major cause of vision loss worldwide. Given the rapid and aggressive nature of the disease, immediate... (Review)
Review
Bacterial keratitis (bacterial infection of the cornea) is a major cause of vision loss worldwide. Given the rapid and aggressive nature of the disease, immediate broad-spectrum antibiotics are essential to adequately treat this disease. However, rising antibiotic resistance continues to accelerate, rendering many commonly used therapeutics increasingly ineffective. As such, there is a significant effort to understand the basic pathogenesis of common causative organisms implicated in keratitis in part, to fuel the development of novel therapies to treat this blinding disease. This review explores two common causes of bacterial keratitis, and , with regards to the bacterial mediators of virulence as well as novel therapies on the horizon.
Topics: Humans; Staphylococcus aureus; Pseudomonas aeruginosa; Staphylococcal Infections; Keratitis; Pseudomonas Infections; Eye Infections, Bacterial
PubMed: 37671149
DOI: 10.3389/fcimb.2023.1250257 -
Microbiology (Reading, England) Sep 2023Antibiotic chemotherapy is widely regarded as one of the most significant medical advancements in history. However, the continued misuse of antibiotics has contributed... (Review)
Review
Antibiotic chemotherapy is widely regarded as one of the most significant medical advancements in history. However, the continued misuse of antibiotics has contributed to the rapid rise of antimicrobial resistance (AMR) globally. , a major human pathogen, has become synonymous with multidrug resistance and is a leading antimicrobial-resistant pathogen causing significant morbidity and mortality worldwide. This review focuses on (1) the targets of current anti-staphylococcal antibiotics and the specific mechanisms that confirm resistance; (2) an in-depth analysis of recently licensed antibiotics approved for the treatment of infections; and (3) an examination of the pre-clinical pipeline of anti-staphylococcal compounds. In addition, we examine the molecular mechanism of action of novel antimicrobials and derivatives of existing classes of antibiotics, collate data on the emergence of resistance to new compounds and provide an overview of key data from clinical trials evaluating anti-staphylococcal compounds. We present several successful cases in the development of alternative forms of existing antibiotics that have activity against multidrug-resistant . Pre-clinical antimicrobials show promise, but more focus and funding are required to develop novel classes of compounds that can curtail the spread of and sustainably control antimicrobial-resistant infections.
Topics: Humans; Anti-Bacterial Agents; Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Anti-Infective Agents; Staphylococcus; Microbial Sensitivity Tests
PubMed: 37656158
DOI: 10.1099/mic.0.001387