Presence of multiple van genes among glycopeptide non-susceptible Staphylococcus aureus exhibiting in vitro MIC creep phenomenon: A study from north-east India.

Background & objectives The global prevalence of vancomycin-resistant Staphylococcus aureus (VRSA) has increased two fold since 2010, accounting for 2.4 per cent of S. aureus infections. The emerging hVISA isolates and their increasing trends pose a serious therapeutic challenge. The present study investigated in vitro vancomycin and teicoplanin minimum inhibitory concentration (MIC) creep in S. aureus and assessed their revertants. Methods A total of 845 isolates were collected for this study, and 246 were confirmed as S. aureus. Molecular characterization of vancomycin resistance was carried out by PCR assay targeting genes types viz: vanA, vanB, vanC, vanC2/C3, vanD, vanE, and vanG. MIC was determined for vancomycin and teicoplanin by agar dilution method. MIC creep and revertant analysis were done by broth dilution method in the presence and absence of antibiotics. Results PCR assay confirmed 12 isolates were harboured vanA, followed by vanD (n=8) and vanB (n=7). The study showed 69 isolates were screened positive for glycopeptide non-susceptibility. While analyzing vancomycin MIC creep, four isolates showed a significant increase in MIC, whereas no creep phenomenon was observed for the rest. In the case of teicoplanin, seven isolates showed the MIC creep phenomenon. Revertant analysis of all the isolates that showed MIC creep phenomenon for vancomycin and teicoplanin reverted to their original MIC when the antibiotic pressure was withdrawn. Interpretation & conclusions In the present study setting, glycopeptide non-susceptibility was found in eight per cent of the isolates, and the present study found the occurrence of multiple van genes from isolates calculated from a single study center will impose a serious challenge in infection control and antibiotic policy. This study also underscores that heterogenic resistant isolates, upon exposure to vancomycin and teicoplanin at a minimum level, exhibited an increase in MIC, which will impact individuals receiving glycopeptide therapy.

A Convenient Diels-Alder Approach toward Potential Polyketide-like Antibiotics Using α-Activated α,ß-Unsaturated 4,4-Dimethyl-1-tetralones as Dienophiles.

Making use of a Diels-Alder approach based on various α,ß-unsaturated 2-carbomethoxy-4,4-dimethyl-1-tetralones as novel dienophiles, the corresponding polycyclic adducts could be efficiently synthesized in good to high yields (74~99%) in the presence of Lewis acid (e.g., SnCl4). Accordingly, a synthetically useful platform is established to provide a focused aromatic polyketide-like library for screening of potential natural and non-natural antimicrobial agents.

A Novel Oral GyrB/ParE Dual Binding Inhibitor Effective against Multidrug-Resistant Neisseria gonorrhoeae and Other High-Threat Pathogens.

Drug-resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance and limit the development of new resistances. Here, we describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6-fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2-oxa-8-azaspiro[4.5]decan-3-yl)methanol], which was developed to target both ATP-binding regions of DNA gyrase (GyrB) and topoisomerase (ParE). JSF-2414 displays potent activity against N. gonorrhoeae, including drug-resistant strains. A phosphate pro-drug, JSF-2659, was developed to facilitate oral dosing. In two different animal models of Neisseria gonorrhoeae vaginal infection, JSF-2659 was highly efficacious in reducing microbial burdens to the limit of detection. The parent molecule also showed potent in vitro activity against high-threat Gram-positive organisms, and JSF-2659 was shown in a deep tissue model of vancomycin-resistant Staphylococcus aureus (VRSA) and a model of Clostridioides difficile-induced colitis to be highly efficacious and protective. JSF-2659 is a novel preclinical drug candidate against high-threat multidrug resistant organisms with low potential to develop new resistance.

High prevalence of MRSA and VRSA among inpatients of Mettu Karl Referral Hospital, Southwest Ethiopia.

OBJECTIVE: To assess the prevalence of methicillin and vancomycin-resistant Staphylococcus aureus among patients admitted to Mettu Karl Referral Hospital. METHODS: A cross-sectional study was conducted to study the point prevalence of MRSA and VRSA. A total of 384 patients (male = 201 and female = 183) admitted to medical (109), paediatric (109) and surgical (166) wards of Mettu Karl Referral Hospital from November 2019 to April 2020 were included in the study. We studied 384 samples (166 wound swabs and 218 nasal swabs) collected from inpatients. Staphylococcus aureus was isolated, characterised and identified based on morphological and biochemical features and confirmed by PCR amplification of the nuc gene. The isolates were checked against 12 antibiotics, and MRSA isolates were primarily identified using cefoxitin (30 µg) and confirmed by amplification of mecA gene. Staphylococcus aureus resistance to Vancomycin was tested by the broth microdilution method. RESULTS: The rate of isolation of Staphylococcus aureus was 32.8% (126/384). The point prevalence of MRSA and VRSA from clinical specimens was 18.8% (72/384) and 2.6% (10/384), respectively. Of 126 Staphylococcus aureus isolated, 57.1% (72) were MRSA and 7.9% (10) were VRSA. Of the 166 samples collected from patients in the surgical ward, the rates of isolation of MRSA and VRSA were 21.1% (35/166) and 4.8% (8/166), respectively. A high rate of isolation of MRSA and VRSA was recorded among patients admitted to surgical wards compared with medical and paediatric wards. CONCLUSIONS: This study showed a high prevalence of MRSA and VRSA in the hospital. Proper implementation of infection control practices and investigation of underlying risk factors are urgently needed to mitigate the further spread of the pathogen.

Genotyping of enterotoxigenic methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA) among commensal rodents in North Sinai, Egypt.

AIM: This study aimed to identify genotype enterotoxigenic antimicrobial-resistant Staphylococcus aureus species, mainly methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) among commensal rodents. METHODS AND RESULTS: A total of 280 samples were collected from nasal and mouth swabs, heart blood, intestinal content and lung tissues of 56 commensal rodents trapped from North Sinai, Egypt. Antimicrobial susceptibility testing was performed to bacteriologically identified S. aureus isolates against 15 antimicrobial agents by disc diffusion method. Detection was conducted for identifying coagulase gene (coA), antimicrobial-resistant genes (mecA and vanA/B), enterotoxigenic and virulence determinant genes (hlg, seb, sed and see) among the MRSA and VRSA isolates. RESULTS: Staphylococcus aureus species were isolated from 24 (42.86%) out of 56 rodents. Phenotypic examination revealed that all the isolates were multidrug-resistant, whereas two isolates were multiple antibiotic resistant (MAR). Out of 33 examined isolates, 33 (100%) were resistant to oxacillin and amoxicillin, 31 (93.93%) to cefoxitin and 12 (36.36%) to vancomycin. PCR assay revealed that 24 isolates revealed (100%) positivity to coA gene, 17 (70.83%) to mecA gene and 12 (50%) to vanA/B genes. Enterotoxin genes and haemolysin genes were detected among MRSA and VRSA isolates. There was a strong positive correlation between the tested antimicrobial-resistant genes and virulence genes (p > 0.05). CONCLUSIONS: This study demonstrated the occurrence of MRSA and VRSA strains among commensal rodents in North Sinai, Egypt. The detection of enterotoxigenic and virulence genes of the isolated MRSA and VRSA strains indicated the health hazards of food contamination and zoonotic infections. SIGNIFICANCE AND IMPACTS OF THE STUDY: This study emphasizes the role of commensal rodents in maintaining and disseminating multidrug-resistant MRSA and VRSA strains to the environment, animals and human beings.

Synthesis and antibacterial evaluation of (E)-1-(1H-indol-3-yl) ethanone O-benzyl oxime derivatives against MRSA and VRSA strains.

Infections caused due to multidrug resistant organisms have emerged as a constant menace to human health. Even though numerous antibiotics are currently available for treating infectious diseases, a great number of bacterial strains have acquired resistance to many of them. Among these, infections caused due to Staphylococcus aureus are predominant in adult and paediatric population. Indole is a prominent chemical scaffold found in many pharmacologically active natural products and synthetic drugs. A number of oxime ether containing compounds have attracted attention of researchers owing to their interesting biological properties. Current work details the synthesis of indole containing oxime ether derivatives and their evaluation for antimicrobial activity against a panel of bacterial and mycobacterial strains. Synthesized compounds demonstrated good to moderate activity against drug-resistant S. aureus including resistant to vancomycin. Among all, compound 5h was found to possess potent activity against susceptible as well as MRSA and VRSA strains of S. aureus with MIC of 1 µg/mL and 2-4 µg/mL respectively. In addition, compound 5h was found to be non-toxic to Vero cells and exhibited good selectivity index of >40. Further, 5h, E-9a and E-9b possessed good biofilm inhibition against S. aureus. With these assuring biological properties, synthesized compounds could be potential prospective antimicrobial agents.

Effect of ZnO nanoparticles on methicillin, vancomycin, linezolid resistance and biofilm formation in Staphylococcus aureus isolates.

BACKGROUND: Multidrug resistant (MDR) and biofilm producing Staphylococcus aureus strains are usually associated with serious infections. This study aimed to evaluate the antibacterial and antibiofilm-formation effects of zinc oxide nanoparticles (ZnO-NPs) against staphylococcus aureus (S. aureus) isolates. METHODS: A total of 116 S. aureus isolates were recovered from 250 burn wound samples. The antimicrobial/antibiofilm effects of ZnO-NPs against methicillin, vancomycin and linezolid resistant S. aureus (MRSA, VRSA and LRSA) isolates were examined using phenotypic and genotypic methods. The minimum inhibitory concentration (MIC) of ZnO-NPs was determined by microdilution method. The effects of sub-MIC concentrations of ZnO-NPs on biofilm formation and drug resistance in S. aureus were determined by the microtiter plate method. The change in the expression levels of the biofilm encoding genes and resistance genes in S. aureus isolates after treatment with ZnO-NPs was assessed by real time reverse transcriptase PCR (rt-PCR). RESULTS: MICs of ZnO-NPs in S. aureus isolates were (128-2048 µg/ml). The sub-MIC of ZnO-NPs significantly reduced biofilm formation rate (the highest inhibition rate was 76.47% at 1024  µg/ml) and the expression levels of biofilm genes (ica A, ica D and fnb A) with P < 0.001. Moreover, Sub-MIC of ZnO-NPs significantly reduced the rates of MRSA from 81.9 (95 isolates) to 13.30% (15 isolates), VRSA from 33.60 (39 isolates) to 0% and LARSA from 29.30 (34) to 0% as well as the expression levels of resistance genes (mec A, van A and cfr) with P value < 0.001. CONCLUSION: ZnO-NPs can be used as antibiofilm and potent antimicrobial against MRSA, VRSA and LRSA isolates.

Tedizolid as Step-Down Therapy following Daptomycin versus Continuation of Daptomycin against Enterococci and Methicillin- and Vancomycin-Resistant Staphylococcus aureus in a Rat Endocarditis Model.

Tedizolid (TZD) and daptomycin (DAP) were assessed in a rat endocarditis model against Enterococcus faecalis, Enterococcus faecium (resistant to vancomycin and ampicillin), and Staphylococcus aureus As a monotherapy, TZD for 5 days was not effective in a comparison with no-treatment controls, while DAP for 5 days was significantly effective against these bacteria. Step-down therapy (DAP for 3 days followed by TZD for 2 days) was as effective as DAP for 5 days and was comparable to 3 days of DAP plus ceftriaxone against all bacteria and to 3 days of DAP plus gentamicin against E. faecalis OG1RF.

Phylogeny of hospital acquired MRSA, and its comparative phenotypic clinico-epidemiology with vancomycin resistant S. aureus (VRSA).

Staphylococcus aureus is emerging as complicated pathogen because of its wide-ranging origin, multiple variants, and compromised antibiotic susceptibilities. Current study was planned to find lineage of hospital acquired methicillin resistant Staphylococcus aureus (HA-MRSA), and its comparative phenotypic clinico-epidemiology with vancomycin resistant S. aureus (VRSA). A total of (n = 200) samples were aseptically collected from wound, nose, and cerebrospinal fluid of patients from metropolitan and rural background hospitals along with on spot filling in of questionnaire. Phylogenetic analysis of HA-MRSA was identified by targeting mecA gene in S. aureus. At optimal tree branch length of 1.91 and evolutionary distance 0.1, high level sequence similarity (97%-99%) was observed with different strains of S. aureus isolated from both human and animal. Non-descriptive statistics at 5% probability found 61% S. aureus, while 43.44% of them were HA-MRSA, 92.62% VRSA, and 42.62% were both MRSA and VRSA. Among assumed risk factors, use of antibiotics, venous catheterization, chronic disease, pre-hospital visits, and ICU admitted patients showed significant association (p<0.05) with pathogen. HA-MRSA was 37.50%, 80%, and 37.50% sensitive to chloramphenicol, gentamicin, and oxacillin, respectively. While <50% of VRSA were sensitive against oxacillin, enoxacin, and chloramphenicol. A significant difference (p<0.05) of percentage responses of MRSA and VRSA at resistant, intermediate, and sensitive cadre against all antibiotics except chloramphenicol was obvious in this study. The Current study concluded higher prevalence of MRSA & VRSA, significant association of risk factors, limiting antibiotic susceptibility profile, and genetic transfer at animal-human interface which suggests further studies cum preventive strategies to be planned.

Single-nucleotide polymorphisms in a vancomycin-resistant Staphylococcus aureus strain based on whole-genome sequencing.

The emergence of vancomycin-resistant Staphylococcus aureus (VRSA) threatens global health. The mechanism of vancomycin resistance of VRSA without vanA gene acquisition was not fully elucidated. Therefore, we aimed to determine the mechanism of vancomycin resistance of VRSA besides that by vanA gene acquisition. In this study, we obtained vancomycin-resistant strains (V036-V64; MIC = 64 µg /ml) from susceptible strain (V036; MIC = 0.5 µg /ml) by exposure of vancomycin in vitro and examined the phenotypic characteristics and antibiotic susceptibility profiles of the resistant strain (V036-V64). To identify the genetic variations caused vancomycin resistance, we determined the complete genome sequences of V036 and V036-V64 and analyzed for single-nucleotide polymorphisms (SNPs) between two strains. Morphologically, V036-V64 had a twofold thicker cell wall compared with V036. Linezolid, rifampicin, and ceftaroline had similar MIC ranges against V036-V64 and V036, but V036-V64 showed lower susceptibilities to daptomycin and telavancin. We detected eight single-nucleotide polymorphisms differing between V036-V64 and V036: rimM (G16D), ssaA2 (G128A), rpsK (P60R), rpoB (R917C), walK (T492R), D-alanyl-D-alanine carboxypeptidase (L307I), vraT (A152V), and chromosome segregation ATPase (T440I). This study demonstrates that, under selective pressure, by the accumulation of mutations in genes related to cell wall synthesis, vancomycin-susceptible S. aureus can develop thicker cell walls and, hence, develop high vancomycin resistance. Thus, we highlight a novel vanA-negative mechanism for VRSA emergence.

Assessment of Vancomycin MIC Creep Phenomenon in Methicillin-Resistant Staphylococcus aureus isolates in a Tertiary Care Hospital of Lahore.

OBJECTIVE: To assess vancomycin MIC creep phenomenon in methicillin-resistant Staphylococcus aureus isolated from clinical specimens. METHODS: This descriptive study was conducted in Microbiology department of University of Health Sciences, Lahore from January 2016- December 2019. In this study, vancomycin MICs were revealed by E test method for clinical MRSA strains. For the final evaluation, a single isolate from each patient was taken. The reported vancomycin MICs results were used and the values were not rounded up to the next upward value. For every study year, MIC50, MIC90, median and geometrical mean MIC, percentages of susceptible and resistant strains were calculated. RESULTS: A total of 352 MRSA strains were isolated out of 2704 staphylococcal isolates. Our study showed elevated vancomycin MIC among MRSA isolates. The majority of isolates showed MIC values ≥1.5µg/ml. MIC50, MIC 90 was constant throughout four years period. However, geometric mean MIC increased gradually during the study period. The MIC greater than base year median was overall 17.3%. A complete shift can be observed between MIC "1.0" and "2.0" the percent of cases with MIC "1.0" decreased and with MIC "2.0" increased over time crossing each other in 2017. CONCLUSION: Vancomycin MIC creep was identified in clinical isolates of MRSA, during four years of study period. Even though there is an absence of VISA and VRSA strains; this significant increase in vancomycin MIC trend is indeed worrying for the clinicians about the threat of potential failure of treatment in MRSA infections.

Disulfiram-based disulfides as narrow-spectrum antibacterial agents.

Sixteen disulfides derived from disulfiram (Antabuse™) were evaluated as antibacterial agents. Derivatives with hydrocarbon chains of seven and eight carbons in length exhibited antibacterial activity against Gram-positive Staphylococcus, Streptococcus, Enterococcus, Bacillus, and Listeria spp. A comparison of the cytotoxicity and microsomal stability with disulfiram further revealed that the eight carbon chain analog was of lower toxicity to human hepatocytes and has a longer metabolic half-life. In the final analysis, this investigation concluded that the S-octylthio derivative is a more effective growth inhibitor of Gram-positive bacteria than disulfiram and exhibits more favorable cytotoxic and metabolic parameters over disulfiram.

Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus.

Antibiotic resistance is a serious threat to global public health, and methicillin-resistant Staphylococcus aureus (MRSA) is a poignant example. The macrolactone natural product albocycline, derived from various Streptomyces strains, was recently identified as a promising antibiotic candidate for the treatment of both MRSA and vancomycin-resistant S. aureus (VRSA), which is another clinically relevant and antibiotic resistant strain. Moreover, it was hypothesized that albocycline's antimicrobial activity was derived from the inhibition of peptidoglycan (i.e., bacterial cell wall) biosynthesis. Herein, preliminary mechanistic studies are performed to test the hypothesis that albocycline inhibits MurA, the enzyme that catalyzes the first step of peptidoglycan biosynthesis, using a combination of biological assays alongside molecular modeling and simulation studies. Computational modeling suggests albocycline exists as two conformations in solution, and computational docking of these conformations to an ensemble of simulated receptor structures correctly predicted preferential binding to S. aureus MurA-the enzyme that catalyzes the first step of peptidoglycan biosynthesis-over Escherichia coli (E. coli) MurA. Albocycline isolated from the producing organism (Streptomyces maizeus) weakly inhibited S. aureus MurA (IC50 of 480 µM) but did not inhibit E. coli MurA. The antimicrobial activity of albocycline against resistant S. aureus strains was superior to that of vancomycin, preferentially inhibiting Gram-positive organisms. Albocycline was not toxic to human HepG2 cells in MTT assays. While these studies demonstrate that albocycline is a promising lead candidate against resistant S. aureus, taken together they suggest that MurA is not the primary target, and further work is necessary to identify the major biological target.

The emergence of vancomycin-resistant Staphylococcus aureus in an intensive care unit in Kerman, Iran.

Methicillin-resistant Staphylococcus aureus (MRSA) is a global threat to public health. This study is the first report of the emergence of vancomycin-resistant MRSA in Kerman, Iran. During a period of 15 months, a total of 205 clinical isolates of S. aureus were collected from three university hospitals affiliated with the Kerman University of Medical Science, Kerman, Iran. Screening of methicillin and vancomycin resistance was carried out by phenotypic methods. The resistance and virulence genes of vancomycin-resistant isolates were detected by polymerase chain reaction (PCR). Staphylococcal cassette chromosome mec (SCCmec) and spa typing were used for molecular typing of vancomycin-resistant isolates. Two S. aureus isolates were considered vancomycin-resistant by phenotypic and genotypic methods. Both isolates showed a minimum inhibitory concentration (MIC) ≥ 64 µg/ml and belonged to SCCmec III and spa type t030. Finding vancomycin-resistant S. aureus (VRSA) isolates represents a serious problem. More stringent infection control policies are recommended to prevent transmission of such life-threatening isolates in the hospital setting.

Repurposing Thiram and Disulfiram as Antibacterial Agents for Multidrug-Resistant Staphylococcus aureus Infections.

Thiram and disulfiram were evaluated as antibacterial agents against multidrug-resistant Staphylococcus aureus Against a 30-member panel comprised of vancomycin-susceptible, vancomycin-intermediate, and vancomycin-resistant S. aureus strains, the MIC90 values of the respective test agents were 4 and 16 µg/ml. Additional analyses revealed that thiram and disulfiram are rapid-acting bacteriostatic agents with narrow, Gram-positive-bacterium spectrum activity. Synergy studies further determined that disulfiram increases the vancomycin susceptibility of three clinical vancomycin-resistant S. aureus strains in vitro, thus establishing a potential use in combination therapy.

Vancomycin Resistance in Staphylococcus aureus
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The evolution of Staphylococcus aureus during the modern antibiotic era has been delineated by distinct strain emergence events, many of which include acquisition of antibiotic resistance. The relative high burden of methicillin-resistant S. aureus (MRSA) in healthcare and community settings is a major concern worldwide. Vancomycin, a glycopeptide antibiotic that inhibits cell wall biosynthesis, remains a drug of choice for treatment of severe MRSA infections. S. aureus strains exhibiting increased resistance to vancomycin, known as vancomycin intermediate-resistant S. aureus (VISA) (MIC = 4-8 µg/mL), were discovered in the 1990s. The molecular basis of resistance in VISA is polygenic and involves stepwise mutations in genes encoding molecules predominantly involved in cell envelope biosynthesis. S. aureus isolates with complete resistance to vancomycin (MIC ≥ 16 µg/mL) are termed vancomycin-resistant S. aureus (VRSA)-they were first reported in the U.S. in 2002. Resistance in VRSA is conferred by the vanA gene and operon, which is present on a plasmid. Although treatment of VRSA infections is challenging, the total number of human VRSA infections to date is limited (14 in the U.S.). By comparison, the burden of VISA is relatively high and the molecular mechanisms of resistance are less well-defined. VISA are associated with persistent infections, vancomycin treatment failure, and poor clinical outcomes. Here, we review in brief progress made toward understanding the acquisition of antibiotic resistance in S. aureus, with an emphasis on the molecular mechanisms underlying vancomycin resistance.

VanA-Type MRSA (VRSA) Emerged in Surface Waters.

Due to the widespread occurrence of mecA-encoded methicillin resistance in Staphylococcus aureus (MRSA), treatment of staphylococcal infections is shifted to glycopeptide antibiotics like vancomycin and teicoplanin. The selective pressure of glycopeptides has eventually led to the emergence of staphylococci with increased resistance. Of great concern is vanA-encoded high level vancomycin and teicoplanin resistance in MRSA (VRSA). Therefore, this study aimed at investigating the occurrence of VRSA in surface waters. Out of 290, two staphylococcal isolates identified as MRSA Al11, Ba01, and one as MRS Co11 through 16S rRNA sequencing, also displayed high level resistance towards vancomycin and teicoplanin. These staphylococcal isolates were found to harbor vanA gene with sequence similarities of 99 %-100 % to the vanA gene extracted from vancomycin- and teicoplanin-resistant enterococcal (VRE) surface water isolates of Enterococcus faecalis Cr07, E07, Pb06 and E. faecium E330. High level glycopeptide resistance rendering protein encoded by the vanA gene, D-alanine-D-lactate ligase found in VRE, was also shown to be present in all vanA-type staphylococcal isolates through western blot. Current study elucidated that surface waters provide high potential for enterococcal vanA gene being transferred to MRSA, so called VRSA, and require special scientific consideration.

Streptogramins - two are better than one!

Streptogramins are potent drugs against numerous highly resistant pathogens and therefore are used as antibiotics of last-resort human therapy. They consist of a mixture of two different types of chemical substances - the group A streptogramins, which are polyunsaturated macrolactones, and the group B streptogramins, representing cyclic hexadepsipeptides. Streptogramins are unique in their mode of action: each component alone exhibits a moderate bacteriostatic activity by binding to the bacterial 50S ribosomal subunit and thereby blocking translation, whereas the synergic combination of both substances is up to hundred fold more effective than the single compounds, resulting in a bactericidal activity. The streptogramin biosynthetic genes are organized as large antibiotic superclusters. These clusters harbour numerous regulatory genes, which encode different types of regulators that together form a complex hierarchical signalling system, which governs the regulation of streptogramin biosynthesis. Resistance is also regulated by this cascade. However, whereas resistance against streptogramins is quite well understood in diverse pathogenic organisms, only little is known about how the natural producer strains protect themselves against these toxic compounds. Here, we give an overview about the recent advances in streptogramin investigations with a main focus on the best-studied representatives, pristinamycin and virginiamycin. We concentrate on the biosynthesis of these compounds, their regulation and resistance determinants as well as their application in medicine and food industry.

Reduced glycopeptide and lipopeptide susceptibility in Staphylococcus aureus and the "seesaw effect": Taking advantage of the back door left open?

Methicillin-resistant S. aureus (MRSA) constitutes approximately 50% of clinical S. aureus isolates and is most commonly the result of production of a mutated pencillin-binding protein, PBP2a, which is able to carry out essential cell wall synthesis functions while maintaining a low-affinity for nearly all beta-lactam antibiotics. Decreased susceptibility to glycopeptides, typically considered first-line MRSA agents, has also been documented. Interestingly, among MRSA isolates, an increase in beta-lactam susceptibility has been documented in the presence of declining lipo- and glycopeptide susceptibility. This phenomenon, termed the "seesaw effect" has been documented both in vitro and in vivo. In the era of increasing antimicrobial resistance and few new drugs to treat these organisms, this phenomenon may provide novel ways to use our current antimicrobials in a new, and more effective, manner.

Pyridine-2,6-Dicarboxamide Proligands and their Cu(II)/Zn(II) Complexes Targeting Staphylococcus Aureus for the Attenuation of In Vivo Dental Biofilm.

In the pursuit to combat stubborn bacterial infections, particularly those stemming from gram-positive bacteria, this study is an attempt to craft a precision-driven platform characterized by unparalleled selectivity, specificity, and synergistic antimicrobial mechanisms. Leveraging remarkable potential of metalloantibiotics in antimicrobial applications, herein, this work rationally designs, synthesizes, and characterizes a new library of Pyridine-2,6-dicarboxamide ligands and their corresponding transition metal Cu(II)/Zn(II) complexes. The lead compound L11 demonstrates robust antibacterial properties against Staphylococcus aureus (Minimum Inhibitory Concentration (MIC) = 2-16 µg mL-1), methicillin and vancomycin-resistant S. aureus (MIC = 2-4 µg mL-1) and exhibit superior antibacterial activity when compared to FDA-approved vancomycin, the drug of last resort. Additionally, the compound exhibits notable antimicrobial efficacy against resistant enterococcus strains (MIC = 2-8 µg mL-1). To unravel mechanistic profile, advanced imaging techniques including SEM and AFM are harnessed, collectively suggesting a mechanistic pathway involving cell wall disruption. Live/dead fluorescence studies further confirm efficacy of L11 and its complexes against S. aureus membranes. This translational exploration extends to a rat model, indicating promising in vivo therapeutic potential. Thus, this comprehensive research initiative has capabilities to transcends the confines of this laboratory, heralding a pivotal step toward combatting antibiotic-resistant pathogens and advancing the frontiers of metalloantibiotics-based therapy with a profound clinical implication.