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Targeting multidrug resistant Staphylococcus infections with bacterial histidine kinase inhibitors.

ABSTRACT: The emergence of drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), which are not susceptible to current antibiotics has necessitated the development of novel approaches and targets to tackle this growing challenge. Bacterial two-component systems (TCSs) play a central role in the adaptative response of bacteria to their ever-changing environment. They are linked to antibiotic resistance and bacterial virulence making the proteins of the TCSs, histidine kinases and response regulators, attractive for the development of novel antibacterial drugs. Here, we developed a suite of maleimide-based compounds that we evaluated against a model histidine kinase, HK853, in vitro and in silico. The most potent leads were then assessed for their ability to decrease the pathogenicity and virulence of MRSA, resulting in the identification of a molecule that decreased the lesion size caused by a methicillin-resistant S. aureus skin infection by 65% in a murine model.

SUBMITTER: Espinasse A

PROVIDER: S-EPMC10189854 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Targeting multidrug resistant <i>Staphylococcus</i> infections with bacterial histidine kinase inhibitors.

Espinasse Adeline A Goswami Manibarsha M Yang Junshu J Vorasin Onanong O Ji Yinduo Y Carlson Erin E EE

Chemical science 20230411 19

The emergence of drug-resistant bacteria, such as methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), which are not susceptible to current antibiotics has necessitated the development of novel approaches and targets to tackle this growing challenge. Bacterial two-component systems (TCSs) play a central role in the adaptative response of bacteria to their ever-changing environment. They are linked to antibiotic resistance and bacterial virulence making the proteins of the TCSs, histidine k ...[more]

PMID: 37206395

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Project description:BackgroundMultidrug-resistant (MDR) bacteria that are commonly associated with health care cause a substantial health burden. Updated national estimates for this group of pathogens are needed to inform public health action.MethodsUsing data from patients hospitalized in a cohort of 890 U.S. hospitals during the period 2012-2017, we generated national case counts for both hospital-onset and community-onset infections caused by methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), extended-spectrum cephalosporin resistance in Enterobacteriaceae suggestive of extended-spectrum beta-lactamase (ESBL) production, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant acinetobacter species, and MDR Pseudomonas aeruginosa.ResultsThe hospital cohort in the study accounted for 41.6 million hospitalizations (>20% of U.S. hospitalizations annually). The overall rate of clinical cultures was 292 cultures per 1000 patient-days and was stable throughout the time period. In 2017, these pathogens caused an estimated 622,390 infections (95% confidence interval [CI], 579,125 to 665,655) among hospitalized patients. Of these infections, 517,818 (83%) had their onset in the community, and 104,572 (17%) had their onset in the hospital. MRSA and ESBL infections accounted for the majority of the infections (52% and 32%, respectively). Between 2012 and 2017, the incidence decreased for MRSA infection (from 114.18 to 93.68 cases per 10,000 hospitalizations), VRE infection (from 24.15 to 15.76 per 10,000), carbapenem-resistant acinetobacter species infection (from 3.33 to 2.47 per 10,000), and MDR P. aeruginosa infection (from 13.10 to 9.43 per 10,000), with decreases ranging from -20.5% to -39.2%. The incidence of carbapenem-resistant Enterobacteriaceae infection did not change significantly (from 3.36 to 3.79 cases per 10,000 hospitalizations). The incidence of ESBL infection increased by 53.3% (from 37.55 to 57.12 cases per 10,000 hospitalizations), a change driven by an increase in community-onset cases.ConclusionsHealth care-associated antimicrobial resistance places a substantial burden on patients in the United States. Further work is needed to identify improved interventions for both the inpatient and outpatient settings. (Funded by the Centers for Disease Control and Prevention.).

Project description:Our objective was to describe the prescribing practices, clinical characteristics, and outcomes of patients treated with ceftolozane-tazobactam (C/T) for multidrug-resistant (MDR) Gram-negative infections. This was a multicenter, retrospective, cohort study at eight U.S. medical centers (2015 to 2019). Inclusion criteria were age ≥18 years and receipt of C/T (≥72 hours) for suspected or confirmed MDR Gram-negative infection. The primary efficacy outcome, evaluated among patients with MDR Pseudomonas aeruginosa infections, was composite clinical failure, namely, 30-day all-cause mortality, 30-day recurrence, and/or failure to resolve or improve infection signs or symptoms after C/T treatment. In total, 259 patients were included, and P. aeruginosa was isolated in 236 (91.1%). The MDR and extremely drug-resistant phenotypes were detected in 95.8% and 37.7% of P. aeruginosa isolates, respectively. The most common infection source was the respiratory tract (62.9%). High-dose C/T was used in 71.2% of patients with a respiratory tract infection (RTI) overall but in only 39.6% of patients with an RTI who required C/T renal dose adjustment. In the primary efficacy population (n = 226), clinical failure and 30-day mortality occurred in 85 (37.6%) and 39 (17.3%) patients, respectively. New C/T MDR P. aeruginosa resistance was detected in 3 of 31 patients (9.7%) with follow-up cultures. Hospital-acquired infection and Acute Physiological and Chronic Health Evaluation II (APACHE II) score were independently associated with clinical failure (adjusted odds ratio [aOR], 2.472 and 95% confidence interval [CI], 1.322 to 4.625; and aOR, 1.068 and 95% CI, 1.031 to 1.106, respectively). Twenty-five (9.7%) patients experienced ≥1 adverse effect (9 acute kidney injury, 13 Clostridioides difficile infection, 1 hepatotoxicity, 2 encephalopathy, and 2 gastrointestinal intolerance). C/T addresses an unmet medical need in patients with MDR Gram-negative infections.

Dataset Information

Targeting multidrug resistant Staphylococcus infections with bacterial histidine kinase inhibitors.

Publications

Targeting multidrug resistant <i>Staphylococcus</i> infections with bacterial histidine kinase inhibitors.

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