The Mechanism of Action of Ginkgolic Acid (15:1) against Gram-Positive Bacteria Involves Cross Talk with Iron Homeostasis.

With the increasing reports of community-acquired and nosocomial infection caused by multidrug-resistant Gram-positive pathogens, there is an urgent need to develop new antimicrobial agents with novel antibacterial mechanisms. Here, we investigated the antibacterial activity of the natural product ginkgolic acid (GA) (15:1), derived from Ginkgo biloba, and its potential mode of action against the Gram-positive bacteria Enterococcus faecalis and Staphylococcus aureus. The MIC values of GA (15:1) against clinical E. faecalis and S. aureus isolates from China were ≤4 and ≤8 µg/mL, respectively, from our test results. Moreover, GA (15:1) displayed high efficiency in biofilm formation inhibition and bactericidal activity against E. faecalis and S. aureus. During its inhibition of the planktonic bacteria, the antibacterial activity of GA (15:1) was significantly improved under the condition of abolishing iron homeostasis. When iron homeostasis was abolished, inhibition of planktonic bacteria by GA (15:1) was significantly improved. This phenomenon can be interpreted as showing that iron homeostasis disruption facilitated the disruption of the functions of ribosome and protein synthesis by GA (15:1), resulting in inhibition of bacterial growth and cell death. Genetic mutation of ferric uptake regulator (Fur) led to GA (15:1) tolerance in in vitro-induced resistant derivatives, while overexpression of Fur led to increased GA (15:1) susceptibility. Additionally, GA (15:1) significantly decreased the bacterial loads of S. aureus strain USA300 in the lung tissues of mice in a pneumonic murine model. Conclusively, this study revealed an antimicrobial mechanism of GA (15:1) involving cross talk with iron homeostasis against Gram-positive pathogens. In the future, the natural product GA (15:1) might be applied to combat infections caused by Gram-positive pathogens. IMPORTANCE The increasing emergence of infectious diseases associated with multidrug-resistant Gram-positive pathogens has raised the urgent need to develop novel antibiotics. GA (15:1) is a natural product derived from Ginkgo biloba and possesses a wide range of bioactivities, including antimicrobial activity. However, its antibacterial mechanisms remain unclear. Our current study found that the function of ferric uptake regulator (Fur) was highly correlated with the antimicrobial activity of GA (15:1) against E. faecalis and that the antibacterial activity of GA (15:1) could be strengthened by the disruption of iron homeostasis. This study provided important insight into the mode of action of GA (15:1) against Gram-positive bacteria and suggested that GA (15:1) holds the potential to be an antimicrobial treatment option for infection caused by multidrug-resistant Gram-positive pathogens.

Linezolid Consumption Facilitates the Development of Linezolid Resistance in Enterococcus faecalis in a Tertiary-Care Hospital: A 5-Year Surveillance Study.

Although case reports and clinical studies of linezolid (LZD)-resistant Enterococcus faecalis (LREF) have gradually increased in recent years, the relationship between LZD resistance and antibiotic consumption in hospital settings still remains unclear. In this study, we aimed to investigate the dynamic relationship between the yearly detection frequency of LREF clinical isolates and yearly consumption of LZD and vancomycin (VCM) over a 5-year period in a Chinese hospital setting. Antibiotic consumption data (LZD and VCM) from 2011 to 2015 were obtained from a computerized database and recalculated as the defined daily doses (DDDs) per 100 bed-days (DBD). All 268 E. faecalis clinical isolates were retrospectively collected from 2011 to 2015 in this hospital. LZD resistance mechanism and multilocus sequence typing of E. faecalis were determined by PCR. The annual detection frequency of LREF clinical isolates tested in this hospital was shown with 1.89% (1/53), 2% (1/50), 2.04% (1/49), 0% (0/45), and 7.04% (5/71), respectively, and the detection frequency of LZD-nonsusceptible E. faecalis (LNSEF; n = 59, including LZD-resistant and intermediate isolates) was determined with 26.42% (14/53), 34% (17/50), 16.33% (8/49), 22.22% (10/45), and 14.08% (10/71), respectively. Spearman correlation analysis revealed that LZD DBD significantly correlated positively with the detection frequency of LREF (r = 0.886, p = 0.019). Moreover, VCM DBD significantly correlated positively with the frequency of LNSEF (r = 0.943, p = 0.005). Furthermore, the detection frequency of optrA-positive E. faecalis also correlated positively with high LZD consumption load in this hospital setting. Conclusively, high LZD consumption load facilitates the development of LZD resistance and promotes the selection of optrA-positive E. faecalis clinical isolates under antibiotic pressure in a hospital setting.