ABSTRACT
A significant increase of hospital-acquired bacterial infections during the COVID-19 pandemic has become an urgent medical problem. Clostridioides difficile is an urgent antibiotic-resistant bacterial pathogen and a leading causative agent of nosocomial infections. The increasing recurrence of C. difficile infection and antibiotic resistance in C. difficile has led to an unmet need for the discovery of new compounds distinctly different from present antimicrobials, while antimicrobial peptides as promising alternatives to conventional antibiotics have attracted growing interest recently. Protein synthesis is an essential metabolic process in all bacteria and a validated antibiotic target. Initiation factor 1 from C. difficile (Cd-IF1) is the smallest of the three initiation factors that acts to establish the 30S initiation complex to initiate translation during protein biosynthesis. Here, we report the solution nuclear magnetic resonance (NMR) structure of Cd-IF1 which adopts a typical ß-barrel fold and consists of a five-stranded ß-sheet and one short α-helix arranged in the sequential order ß1-ß2-ß3-α1-ß4-ß5. The interaction of Cd-IF1 with the 30S ribosomal subunit was studied by NMR titration for the construction of a structural model of Cd-IF1 binding with the 30S subunit. The short α-helix in IF1 was found to be critical for IF1 ribosomal binding. A peptide derived from this α-helix was tested and displayed a high ability to inhibit the growth of C. difficile and other bacterial strains. These results provide a clue for the rational design of new antimicrobials.IMPORTANCEBacterial infections continue to represent a major worldwide health hazard due to the emergence of drug-resistant strains. Clostridioides difficile is a common nosocomial pathogen and the causative agent in many infections resulting in an increase in morbidity and mortality. Bacterial protein synthesis is an essential metabolic process and an important target for antibiotic development; however, the precise structural mechanism underlying the process in C. difficile remains unknown. This study reports the solution structure of C. difficile translation initiation factor 1 (IF1) and its interaction with the 30S ribosomal subunit. A short α-helix in IF1 structure was identified as critically important for ribosomal binding and function in regulating the translation initiation, which allowed a rational design of a new peptide. The peptide demonstrated a high ability to inhibit bacterial growth with broad-spectrum antibacterial activity. This study provides a new clue for the rational design of new antimicrobials against bacterial infections.
Subject(s)
Bacterial Infections , Clostridioides difficile , Humans , Antimicrobial Peptides , Cadmium , Pandemics , Peptide Initiation Factors , Anti-Bacterial Agents/pharmacologyABSTRACT
BACKGROUND: Myocardial hypertrophy is a compensatory mechanism in patients with severe aortic stenosis. The left ventricle fits the systolic pressure through a hypertrophic process with increased wall thickness. The effects of elevated ventricular afterload reduce ventricular myocardial elasticity and decrease coronary flow with increased myocardial work, oxygen consumption, and mortality. Aortic valve replacement surgery can cause regression of left ventricular hypertrophy and improve patient survival. The aim of this study was to evaluate left ventricular adaptive response after surgery of aortic valve replacement for severe valvular stenosis. MATERIAL AND METHODS: An observational, analytical, longitudinal study that included patients with diagnosis of aortic stenosis with evidence of left ventricular hypertrophy undergoing valve replacement during the period January 2013 to September 2014. Echocardiographic studies were performed before surgery and six months thereafter. Pre- and postoperative means were compared with Student t test for related samples. Statistical significance was considered at p ≤ 0.05. RESULTS: 24 patients were included, with an average age of 57.5 years, with no gender predominance, of which 87.5% had history of smoking and 50% with hypertension. There was no statistically significant difference in diastolic and systolic diameter before and after surgery. The interventricular septum was 14.9 ± 2.3 mm preoperative and 12.8 ± 2.2 mm postoperative (p = 0.001). The back wall was 14.2 ± 1.8 mm preoperative and 12.5 ± 2.2 mm postoperative (p = 0.002). The ventricular mass before surgery was 154.8 ± 54.3 g/m(2) and then 123.2 ± 41.4 g/m(2) (p = 0.000). The maximum preoperative transvalvular gradient was 93 ± 35 mmHg and postoperative was 32.2 ± 14.4 mmHg (p = 0.00). The average preoperative transvalvular gradient was 56.3 ± 19 mmHg and postoperative was 7.5 ± 16.49 mmHg (p = 0.00). CONCLUSIONS: The interventricular septum, posterior wall, and left ventricular mass decreased significantly after aortic valve replacement. The maximum and mean transvalvular gradient decreased significantly after surgery for aortic valve replacement.
