Zidebactam restores sulbactam susceptibility against carbapenem-resistant Acinetobacter baumannii isolates.

Carbapenems are commonly used to treat infections caused by multidrug-resistant (MDR) bacteria. Unfortunately, carbapenem resistance is increasingly reported in many gram-negative bacteria, especially Acinetobacter baumannii. Diazabicyclooctane (DBO) ß-lactamase inhibitors, such as avibactam (AVI), when combined with sulbactam successfully restore sulbactam susceptibility against certain carbapenem-resistant A. baumannii (CRAB) isolates. In the present study, we tested zidebactam, a novel DBO with an additional mechanism of action, in combination with sulbactam against CRAB isolates, including strains that exhibited resistance against sulbactam/avibactam combination. A panel of 43 geographically and genetically distinct CRAB isolates recovered from different hospitals and containing different mechanisms of resistance were included in the present study. We also tested three reference strains (AB0057, AB5075, and AYE). Minimum inhibitory concentrations (MICs) for sulbactam (range 0.12-512 mg/l) and sulbactam plus 4 mg/l zidebactam were performed using microdilution according to CLSI Standards. A decrease ≥2 dilutions in sulbactam MICs was observed in 84% of the isolates when tested in combination with zidebactam. The sulbactam/zidebactam combination was able to restore sulbactam susceptibility in 91% of the isolates, including isolates that were resistant to sulbactam/avibactam combination. These data encouraged us to further explore sulbactam/zidebactam in other experimental models especially against CRAB isolates resistant to other DBOs.

A New Twist: The Combination of Sulbactam/Avibactam Enhances Sulbactam Activity against Carbapenem-Resistant Acinetobacter baumannii (CRAB) Isolates.

An increasing number of untreatable infections are recorded every year. Many studies have focused their efforts on developing new ß-lactamase inhibitors to treat multi-drug resistant (MDR) isolates. In the present study, sulbactam/avibactam and sulbactam/relebactam combination were tested against 187 multi-drug resistant (MDR) Acinetobacter clinical isolates; both sulbactam/avibactam and sulbactam/relebactam restored sulbactam activity. A decrease ≥2 dilutions in sulbactam MICs was observed in 89% of the isolates when tested in combination with avibactam. Sulbactam/relebactam was able to restore sulbactam susceptibility in 40% of the isolates. In addition, the susceptibility testing using twenty-three A. baumannii AB5075 knockout strains revealed potential sulbactam and/or sulbactam/avibactam target genes. We observed that diazabicyclooctanes (DBOs) ß-lactamase inhibitors combined with sulbactam restore sulbactam susceptibility against carbapenem-resistant Acinetobacter clinical isolates. However, relebactam was not as effective as avibactam when combined with sulbactam. Exploring novel combinations may offer new options to treat Acinetobacter spp. infections, especially for widespread oxacillinases and metallo-ß-lactamases (MBLs) producers.

Aminoglycoside 6'-N-acetyltransferase Type Ib [AAC(6')-Ib]-Mediated Aminoglycoside Resistance: Phenotypic Conversion to Susceptibility by Silver Ions.

Clinical resistance to amikacin and other aminoglycosides is usually due to the enzymatic acetylation of the antimicrobial molecule. A ubiquitous resistance enzyme among Gram-negatives is the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib], which catalyzes acetylation using acetyl-CoA as a donor substrate. Therapies that combine the antibiotic and an inhibitor of the inactivation reaction could be an alternative to treat infections caused by resistant bacteria. We previously observed that metal ions such as Zn2+ or Cu2+ in complex with ionophores interfere with the AAC(6')-Ib-mediated inactivation of aminoglycosides and reduced resistance to susceptibility levels. Ag1+ recently attracted attention as a potentiator of aminoglycosides' action by mechanisms still in discussion. We found that silver acetate is also a robust inhibitor of the enzymatic acetylation mediated by AAC(6')-Ib in vitro. This action seems to be independent of other mechanisms, like increased production of reactive oxygen species and enhanced membrane permeability, proposed to explain the potentiation of the antibiotic effect by silver ions. The addition of this compound to aac(6')-Ib harboring Acinetobacter baumannii and Escherichia coli cultures resulted in a dramatic reduction of the resistance levels. Time-kill assays showed that the combination of silver acetate and amikacin was bactericidal and exhibited low cytotoxicity to HEK293 cells.

Gartanin is a novel NEDDylation inhibitor for induction of Skp2 degradation, FBXW2 expression, and autophagy.

Gartanin, a 4-prenylated xanthone, has been identified from the purple mangosteen fruit as a potent growth inhibitor of various cancer cell lines, including prostate cancer. However, much of Gartanin's anticancer mechanism remains unknown. We have discovered that Gartanin docked onto the regulatory subunit of the precursor cell-expressed developmentally downregulated 8 (NEDD8)-activating enzyme (NAE) complex and next to the NEDD8 binding complex, which leads to inhibit NEDD8 conjugations to both Cullin1 and Ubc12 in prostate cancer cell lines and Ubc12 NEDDylation in an in vitro assay. The S phase kinase-associated protein (Skp2) and F-box and WD-repeat domain-containing 2 (FBXW2), the NEDD8 family members of E3 ubiqutin ligases, were also downregulated and upregulated by Gartainin, respectively. Knock-down of NEDD8 expression by short harpin (Sh) RNAs blocked or attenuated these effects of Gartainin. Finally, Gartanin demonstrated its ability to inhibit growth of prostate cancer lines via autophagy initiation. Our data support that Gartanin is a naturally occurring NEDDylation inhibitor and deserves further investigation for prostate cancer prevention and treatment.

"It's not rocket science, what I do": Self-directed harm reduction strategies among drug using ethno-racially diverse gay and bisexual men.

BACKGROUND: Research on harm reduction has typically focused on broad-based or organisational strategies such as needle exchange and opiate substitute programmes. Less attention has been paid to the self-directed harm reduction practices of substance users themselves. Few studies have focused on sexual minority populations such as gay and bisexual men and fewer still on the marginalised groups that constitute these populations. This paper identifies self-directed harm reduction strategies among substance using ethno-racially diverse gay and bisexual men. METHODS: This article presents findings from the Party Drugs Study in Toronto's gay dance club scene, a community-based qualitative study in Toronto, Canada. We present a thematic analysis of interviews with 43 gay and bisexual men from diverse ethno-racial backgrounds about their substance use in the gay dance club scene. FINDINGS: We identify five self-directed harm reduction strategies: rationing, controlling or avoiding mixing, controlling quality, maintaining a healthy lifestyle, and following guidelines during substance use. CONCLUSIONS: We discuss our findings in relation to prior research and to critical theory. We suggest that drug users' awareness of possible harm, and their personal investment in harm reduction, constitute a viable platform from which community-based and public health organisations may promote and strengthen harm reduction among gay and bisexual men from ethno-racially diverse backgrounds.