Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century

Abstract

Chloroquine (CQ) and its hydroxyl analogue hydroxychloroquine (HCQ) are weak bases with a half-century long use as antimalarial agents. Apart from this antimalarial activity, CQ and HCQ have gained interest in the field of other infectious diseases. One of the most interesting mechanisms of action is that CQ leads to alkalinisation of acid vesicles that inhibit the growth of several intracellular bacteria and fungi. The proof of concept of this effect was first used to restore intracellular pH allowing antibiotic efficacy for Coxiella burnetii, the agent of Q fever, and doxycycline plus HCQ is now the reference treatment for chronic Q fever. There is also strong evidence of a similar effect in vitro against Tropheryma whipplei, the agent of Whipple's disease, and a clinical trial is in progress. Other bacteria and fungi multiply in an acidic environment and encouraging in vitro data suggest that this concept may be generalised for all intracellular organisms that multiply in an acidic environment. For viruses, CQ led to inhibition of uncoating and/or alteration of post-translational modifications of newly synthesised proteins, especially inhibition of glycosylation. These effects have been well described in vitro for many viruses, with human immunodeficiency virus (HIV) being the most studied. Preliminary in vivo clinical trials suggest that CQ alone or in combination with antiretroviral drugs might represent an interesting way to treat HIV infection. In conclusion, our review re-emphasises the paradigm that activities mediated by lysosomotropic agents may offer an interesting weapon to face present and future infectious diseases worldwide.

Abnormal Weight Gain and Gut Microbiota Modifications Are Side Effects of Long-Term Doxycycline and Hydroxychloroquine Treatment

“…The administration of hydroxychloroquine leads to the alkalinization of intracellular acid vesicles that inhibit the growth of several intracellular organisms, facilitating antibiotic efficacy for Coxiella burnetii and Tropheryma whipplei (14,30). Moreover, in vitro data have suggested that the effects of hydroxychloroquine might be generalized for Borrelia burgdorferi (31) and all intracellular organisms that multiply in acidic environments (32). Although antimalarials are generally inactive against most extracellular bacterial species (33), a direct antibacterial effect has been demonstrated, with an in vitro inhibitory effect on the bacterial DNA polymerase of E. coli and Micrococcus luteus (34,35).…”

Impact of Hydroxychloroquine-Loaded Polyurethane Intravaginal Rings on Lactobacilli

“…2A). Concentrations higher than 1 mg/ml significantly inhibited the growth of both strains, which could be attributable to the bacteriostatic effects of HCQ (36). Therefore, the level of HCQ released from our device is significantly lower than the levels that inhibit the growth of lactobacilli but is high enough to elicit a therapeutic effect within the FGT.…”

Prevention of Infection in Lupus Patients

“…SLE patients taking antimalarials are 16 times less likely to develop a major infection [46,47]. SLE patients who require more potent medications (corticosteroids or cytotoxic drugs) may still benefit from antimalarials, as they reduce infection rate, mortality, and have few side effects [4].…”