Antibacterial Mechanisms and Efficacy of Sarecycline in Animal Models of Infection and Inflammation

Abstract

Prolonged broad-spectrum antibiotic use is more likely to induce bacterial resistance and dysbiosis of skin and gut microflora. First and second-generation tetracycline-class antibiotics have similar broad-spectrum antibacterial activity. Targeted tetracycline-class antibiotics are needed to limit antimicrobial resistance and improve patient outcomes. Sarecycline is a narrow-spectrum, third-generation tetracycline-class antibiotic Food and Drug Administration (FDA)-approved for treating moderate-to-severe acne. In vitro studies demonstrated activity against clinically relevant Gram-positive bacteria but reduced activity against Gram-negative bacteria. Recent studies have provided insight into how the structure of sarecycline, with a unique C7 moiety, interacts with bacterial ribosomes to block translation and prevent antibiotic resistance. Sarecycline reduces Staphylococcus aureus DNA and protein synthesis with limited effects on RNA, lipid, and bacterial wall synthesis. In agreement with in vitro data, sarecycline demonstrated narrower-spectrum in vivo activity in murine models of infection, exhibiting activity against S. aureus, but reduced efficacy against Escherichia coli compared to doxycycline and minocycline. In a murine neutropenic thigh wound infection model, sarecycline was as effective as doxycycline against S. aureus. The anti-inflammatory activity of sarecycline was comparable to doxycycline and minocycline in a rat paw edema model. Here, we review the antibacterial mechanisms of sarecycline and report results of in vivo studies of infection and inflammation.

Keywords: acne; animal models; antibiotic; antibiotic resistance; infection; inflammation; narrow-spectrum; sarecycline; tetracyclines.

Figure 1

Chemical structures of the different tetracycline-class drugs used for the treatment of acne vulgaris: tetracycline, doxycycline, minocycline, and sarecycline. The incorporation of a longer C7 moiety allows sarecycline to interact more strongly with the bacterial ribosome. Structure image source: http://www.chemspider.com/Chemical-Structure.28540486.html (accessed on 14 April 2021).

Figure 2

Atomic resolution crystallographic structure of sarecycline in complex with the bacterial 70S ribosome. (A–C) Overview of the SAR binding site (yellow) on the T. thermophilus 70S ribosome viewed from three different perspectives. The 30S subunit is shown in light gray, the 50S subunit is dark gray, the mRNA is magenta, and the P site tRNA is colored dark blue. In A, the 30S subunit is viewed from the intersubunit interface, as indicated by Inset (the 50S subunit and parts of the P site tRNA are removed for clarity). The view in B is a transverse section of the 70S ribosome. The view in C is from the top after removing the head of the 30S subunit and protuberances of the 50S subunit, as indicated by Inset. Red boxes in (D–F) indicate the C7 moiety of sarecycline. mRNA is shown in purple. Image used with permission from [26].

Figure 3

Effect of sarecycline on macromolecular biosynthesis in (A) DNA synthesis, (B) RNA synthesis, (C) protein synthesis, (D) lipid synthesis, and (E) cell wall synthesis in S. aureus ATCC 29213. DNA, RNA, protein, cell wall, and lipid synthesis was determined by measuring incorporation of (3H)thymidine, (3H)uridine, (3H)leucine, (3H)Nacetylglucosamine, and (3H)glycerol, respectively. Control agents included ciprofloxacin (a DNA synthesis inhibitor), linezolid (a protein synthesis inhibitor), cerulenin (a lipid synthesis inhibitor), vancomycin (a cell wall biosynthesis inhibitor), and rifampin (a RNA synthesis inhibitor). Data represent the median with 95% confidence intervals (n = 3). Image used with permission from [30].

Figure 4

Minimum inhibitory concentration required to inhibit the growth of 50% of organisms (MIC₅₀) of sarecycline and other tetracycline-class antibiotics in (A) Gram-positive bacteria and (B) Gram-negative bacteria. The lower the MIC₅₀, the more effective the antibiotic against that bacterial type. Data originally reported in [30].

Figure 4

Minimum inhibitory concentration required to inhibit the growth of 50% of organisms (MIC₅₀) of sarecycline and other tetracycline-class antibiotics in (A) Gram-positive bacteria and (B) Gram-negative bacteria. The lower the MIC₅₀, the more effective the antibiotic against that bacterial type. Data originally reported in [30].