Doxycycline: Definition, Mechanism and Application

What type of antibiotic is doxycycline?

Doxycycline (DOX) is a semi-synthetic tetracycline antibiotic used to treat mild to moderate infections caused by susceptible microorganisms. It is a synthetic derivative of oxytetracycline (a natural substance produced by Streptomyces) whose main function is bacteriostasis, that is, inhibiting bacterial growth rather than killing bacteria directly. Doxycycline, like other tetracyclines, is active against broad-spectrum gram-positive and gram-negative bacteria, as well as several rickettsiae, spirochaetes, chlamydia, and mycoplasma. Unlike tetracycline and oxytetracycline, doxycycline cyclophosphamide has good oral effectiveness and extensive tissue permeability. Indications include upper respiratory tract, skin or soft tissue infections caused by susceptible bacteria, gonorrhea and syphilis in patients with penicillin allergy, non-gonococcal urethritis, acute pelvic inflammatory disease, epididymitis, orchitis, Lyme disease, and, as a preventive measure, holy Traveler's diarrhea. Doxycycline has also long been used to treat acne. Doxycycline was approved for use in the United States in 1967 and is still widely used today, with more than 11 million prescriptions written each year.

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Mechanism of action of doxycycline

Doxycycline and other tetracycline drugs enter bacterial cell walls in two ways: passive diffusion and an energy-dependent active transport system, the latter of which may be mediated by a pH-dependent manner. Once inside the cell, tetracyclins can reversibly bind to the 30S subunit A position of the bacterial ribosome, thereby preventing aminoacyl-trNA from binding to the receptor site on the MRNA-ribosome complex. This effect prevents the addition of new amino acids to the growing peptide chain, and ultimately inhibits bacterial protein synthesis.

In recent years, research has investigated doxycycline's potential role in cancer treatment. Some studies suggest that it can inhibit cancer cell proliferation, promote apoptosis (programmed cell death), and block the G1 phase in the cell cycle. By interrupting the cellular processes that drive tumor growth, doxycycline may act as an adjunctive therapy in cancer treatments. While more research is needed to confirm these findings, the antibiotic's ability to cross cellular membranes and act on a wide range of tissues makes it a promising candidate for future oncological applications.

What is doxycycline used for?

Doxycycline has received approval from the Food and Drug Administration (FDA) to prevent or treat certain conditions across various categories, including rickettsial infections, sexually transmitted infections, respiratory tract infections (such as bronchitis, pneumonia, or sinusitis), bacterial infections, Lyme disease, eye infections, anthrax, acute intestinal amebiasis, traveler's diarrhea, and severe acne.

Doxycycline antibiotics for sinus infection

Even though it might not be the definitive therapy, this antibiotic continues to get used often when other antibiotics have failed. This covers very common sinus pathogens such as Streptococcus pneumoniae and Haemophilus influenzae, giving lasting relief to resistance cases.

Doxycycline for malaria

Doxycycline has become an important tool in the prophylaxis against malaria, especially after its FDA approval for this indication on 1994. This recommendation is guided by a strong body of research evidence supporting its safety and effectiveness across different populations, including among military personnel in areas where the disease is endemic. There are a number of studies on the pharmacokinetics and safety of doxycycline in long term. For instance, a survey of Australian military personnel deployed in Cambodia and Somalia indicated that doxycycline was well tolerated, with discontinuation rates due to adverse effects being relatively low (0.6% to 1.7%).

Doxycycline for Hutchinson-Gilford progeria syndrome (HGPS)

HGPS is caused by A mutation in the Lmna gene that produces the shortened mutant lamin A precursor protein progerin. Zmpste24 is A protease that processes the Lamin A precursor protein to mature, and its deletion causes premature aging, with a phenotype very similar to that of HGPS progeria. Therefore, Zmpste24 knockout (KO) mice have been widely used as mouse models of HGPS progeria in the study of the molecular mechanism and drug therapy of HGPS progeria.

Wang Ming et al. showed that DOX can prolong the life span of HGPS progeria model mice, and improve the related characteristics of progeria such as weight loss, reduced exercise ability, reduced bone density, and shortened colorectal. DOX reduces the expression of pro-inflammatory factor IL6 in serum and tissue of progeria mice, and delays the senescence and death of MEF cells of progeria mice and skin tissue cells of HGPS patients. In addition, DOX reduced the over-acetylation of alpha-type microtubules in progeria cells and in pregeria mouse arterial arch cells. DOX has anti-HGPS progeria effect and can be used as potential drugs for the treatment of HGPS.

Schematic diagram of doxycycline decelerates aging in progeria mice. (Wang, M., 2024)

Doxycycline controls NLRP3-mediated inflammation

The NLRP3 inflammator is a multiprotein complex that plays a key role in the inflammatory process of a variety of diseases. Doxycycline, a ribosomal targeting antibiotic (RAbo), It can effectively inhibit mitochondrial translation, NLRP3 inflammatory body mediated caspase-1 activation and interleukin-1β (IL-1β) production. By knocking down mitochondrial formyl-trNA synthase (Mtfmt), a key rate-limiting enzyme in mitochondrial translation, NLRP3 inflammator-mediated caspase-1 activation and IL-1β secretion were also inhibited. Both doxycycline treatment and Mtfmt knockdown blocked the synthesis of mitochondrial DNA (mtDNA) and the production of oxidized mtDNA (Ox-mtDNA), a ligand activated by the NLRP3 inflammatory body. In vivo experiments, doxycycline mitigated the NLRP3 dependent inflammatory response, including LPS-induced systemic inflammation and endometritis. In summary, doxycycline effectively alleviates the activation of NLRP3 inflammatorites and related inflammatory responses by inhibiting mitochondrial translation and mtDNA synthesis, providing a new therapeutic strategy for the treatment of NLRP3-mediated diseases. This study revealed that in addition to the antibacterial effect, antibiotics can also regulate the inflammatory response by affecting the mitochondrial function of host cells, providing a new scientific basis for the application of antibiotics in the field of non-antibacterial therapy.

Potential role in cancer treatment

Preliminary studies have shown that doxycycline may suppress tumor growth by inhibiting matrix metalloproteinases (MMPs), enzymes that degrade the extracellular matrix and promote metastasis. Additionally, doxycycline has been shown to interfere with mitochondrial function in cancer cells, leading to energy depletion and increased susceptibility to apoptosis. While these findings are promising, further clinical research is required to validate doxycycline's efficacy in cancer treatment.

References

1. Styka, A.N. and Savitz, D.A. Assessment of long-term health effects of antimalarial drugs when used for prophylaxis. Washington (DC): National Academies Press (US). 2020 Feb 25. 7, Doxycycline.
2. Wang, M., et al. Doxycycline decelerates aging in progeria mice. Aging Cell. 2024, 23: e14188.
3. Liu, S., et al. Ribosome-targeting antibiotic control NLRP3-mediated inflammation by inhibiting mitochondrial DNA synthesis. Free Radical Biology and Medicine. 2024, 210: 75-84.