Table 1.

Past studies exploring the anti-chlamydial properties of non-antibiotic approaches.

Category	Designation	Chlamydial specie	Model	Antibacterial mechanism	Shortcomings*
Synthetic Drugs	Broad-Spectrum Antiviral Compound ST-669	C. trachomatis; C. pneumoniae	Vero cells; HeLa cells; McCoy cells	•Affecting intracellular growth in a host-cell-dependent manner; •Interrupting the normal development of chlamydial inclusions through lipid droplet-dependent processes	•The efficacy is hard to predict
	Designated compound 1 (C1); A small-molecule inhibitor of type III secretion INP0400	C. trachomatis	HeLa 229 epithelial cells; McCoy cells; Mouse vaginal infection model	•Inhibiting RB to EB differentiation; •Inhibiting the type III secretion system of Chlamydia	•The efficacy and pharmacokinetics properties are hard to predict
	Lipopolysaccharide-Binding Alkylpolyamine DS-96	C. trachomatis	HeLa 229 cells	•This effect can be manifested at an early stage; •Inhibition of EB attachment and entry by binding to lipooligosaccharide (LOS)	•Has cell toxicity, and toxicity studies need to be further investigated
	Synthetic polymers PSS and SPS	C. trachomatis; C. muridarum	HeLa 229 cells Female outbred Swiss Webster mice	•Effectively block the chlamydial attachment and/or reduce host-pathogen interactions; •The antichlamydial effect of these drugs performed in a concentration-dependent manner	•No sigmoid curve or absolute infection prophylaxis was observed with SPGG at any increase
Polyphenols	Baicalin Luteolin Catechins n	C. trachomatis C. pneumoniae C. pneumoniae	Hep-2 cells; C57BL/6 mice C57BL/6J mice HeLa 229 cells	•Inhibiting phosphorylation cascades; •Reducing the production of chemokines; •Damage the plasma membrane by destroying the permeability of the lipid bilayer	•High concentrations of this class of compounds are cytotoxic
Category	Designation	Chlamydial specie	Model	Targeting aspects of chlamydial infection	Shortcomings *
Lipidic	Five active synthetic lipids; 3-O-octyl-sn-glycerol [3-OG]; Fatty Acids and Monoglycerides	C. trachomatis	McCoy cells; Mouse fibroblast cells; McCoy mouse fibroblast cells; McCoy cells	•Destroying the membrane of the pathogen to inhibit the infection	•High concentrations of this class of compounds are cytotoxic
Peptides	Transferrin; WLBU2 Peptide; Cecrotin peptides; Cathelicidin peptides; Spider venom peptides; Antimicrobial Peptide Melittin	C. psittaci; C. trachomatis; 25 Chlamydia strains	HD11 cells; McCoy cells; Turkeys; McCoy mouse fibroblast cells; LLC-MK2 cells; Human red blood cells; HeLa cells; HEK293 cells	•Interfering with the Chlamydia adhesion to cells through decreasing transmembrane potential of host cells	•The therapeutic effect is slow, slower than conventional antibiotic therapy
Immune substances – cytokines	Interferon-γ (IFN-γ); Tumor Necrosis Factor (TNF); Interleukin (IL-4, IL-1α, IL-10, IL-23)	C. muridarum; C. trachomatis; C. pneumoniae	BALB/c mice; C57BL/6 mice; TNFR1 mice; C57BL/6 mice; TNFR1 mice; C57BL/6 mice	•Enhancing host immune response; •Infection can be directly restricted by inducing tryptophan catabolism and nitric oxide	•The pleiotropy of cytokine receptors and undesired activation of off-target cells
Vaccines	Subunit peptide vaccine; Recombinant vaccine; Mucosal vaccine**	C. muridarum C. trachomatis	Female BALB/c mice; C57BL/6 mice; C57BL/6 and BALB/c mice	•Preventing early infection •Shortening the duration of infection	•Causing abnormal host immune response

^*All therapies still are preclinical.

^**In Clinical trial 1 phase as a prophylactic vaccine.