4. Discussion
infection
ACUTE INFECTION, CYTOMEGALOVIRUS RETINITIS, INFECTION
Although the SONIA 2 clinical trial indicated that HGA should be evaluated as part of an antibiotic discovery program, early promise was not borne out during in vitro microbiological and safety evaluations. This serves as a reminder that it is necessary to carry out early in vitro feasibility studies, even when the compound under investigation is naturally occurring in humans. The presence of modest antibacterial activity at HGA concentrations that induce cytotoxic effects in cultured human cells indicates that the compound does not display specific inhibition of bacteria. Furthermore, as HGA is converted to BQA more quickly under alkaline conditions, such as those found in the small intestine, orally dosed HGA would likely not be absorbed sufficiently to reach the systemic circulation at concentrations that exert antibacterial effects. Modifying the HGA molecule to increase its potency and bioavailability in order to attain safe circulating concentrations has not yet been explored. In an alternative approach, HGA could be utilised via innovative gene silencing techniques, employing a transient knock down of the homogentisate 1,2-dioxygenase gene in vivo using siRNA, temporarily increasing HGA systemically during an acute infection. Proof of concept for the use of antisense oligonucleotides as antimicrobial therapies was first achieved for the treatment of cytomegalovirus retinitis [In view of the data presented here, HGA is not a viable candidate for development as a systemic antibiotic, its properties rendering the compound more appropriate for use as a topical antimicrobial agent if used in its current form. There is a precedent for the use of membrane-damaging antimicrobials in healthcare products, such as 1% silver sulfadiazine cream, for the treatment of burn wounds. When applied at high concentrations at the site of infection, compounds that disrupt bacterial membranes are less likely to select for highly drug-resistant organisms and circumvent any potential systemic tolerability liabilities, as is the case for silver sulfadiazine [