Insight into innovative approaches to battle Acinetobacter baumannii infection therapy struggles

The genus Acinetobacter comprises a wide collection of species with most of them residing in the environment and causing no harm to humans. However, almost 50 years ago a member of this family was identified as the causative agent of septicemia.¹ Since then, more than 2,400 PubMed reports associate this bacterium with human infections, describing A. baumannii and related isolates as the main cause of disease. Initially, A. baumannii was associated with nosocomial infections as well as infections in compromised patients. However, in the last few years A. baumannii has emerged as a more aggressive pathogen representing a serious threat to not only the nosocomial civilian population but also as a relevant threat to military personnel wounded in the Middle East.² Unexpectedly, it was also found as the sole cause of two human necrotizing fasciitis cases reported early this year,³ although a fatal case affecting a cat was reported two years ago.⁴ The extensive number of publications, more than 2,500 PubMed reports since 1965, revealed the ability of this pathogen to resist antibiotics by a wide range of mechanisms. This situation has become very serious because of the increasing number of worldwide reports describing multidrug-resistant A. baumannii isolates refractory to most if not all conventional antimicrobial regimens used in human therapy. Clearly, this outcome together with the rather poor understanding of the A. baumannii virulence factors that play a role in the pathogenesis of the infections it causes in humans pose a serious medical challenge. These problems are further compounded by the significant differences in the expression of cell properties, such as biofilm formation, motility on semi-solid surfaces, production of multiple cell appendages and cell surface properties among different clinical isolates (McQueary and Actis LA, submitted for publication). These differences could well reflect the apparent variations in virulence phenotype among clinical isolates, when tested in a rodent animal model, which were recently reported.⁵ Altogether, these factors and situations pose a serious challenge in the development of convenient and effective therapeutic approaches to treat human infections caused by A. baumannii.

In response to some of the aforementioned challenges, new therapeutic approaches that avoid the emergence of bacterial resistance responses have been developed recently. One of these novel approaches is reported in this issue of Virulence, in which nanoparticles capable of generating nitric oxide were used to treat A. baumannii murine wound experimental infections. It is apparent that these nanoparticles not only act as an effective antibacterial tool but also stimulate a protective immune response and accelerate wound healing by inhibiting collagen degradation. This is an encouraging outcome since it suggests that nitric oxide producing nanoparticles could be used for the treatment of wound infections caused by A. baumannii, such as those described in wounded soldiers, without the potential risks of resistance to additional antimicrobial compounds. Although the results obtained using a relevant vertebrate animal model are encouraging, the therapeutic efficacy and the potential secondary effects of this type of nanoparticles in the human host remain to be determined. Equally encouraging is the photodynamic approach recently developed with the purpose of also treating localized infections caused by an A. baumannii clinical Iraqi isolate.⁶ While these two novel approaches have the potential to serve as topical treatments of localized surface exposed infections, much less has been done to address the treatment of A. baumannii systemic infections with therapeutic agents different from classical and routine antibiotics. It seems that essential cellular functions, such as those expressed by A. baumannii to acquire iron from host sources,⁷ could be a viable alternative target not only because of the role some of the components of the iron acquisition systems play in these processes but also because of the possibility of blocking the functionality of proteins that depend on the redox chemistry of iron. In this regard, it has been shown that Gallium is an effective agent to treat infections caused by A. baumannii as well as Pseudomonas aeruginosa and Staphylococcus aureus in thermally injured mice.⁸ Although these are interesting and promising observations, the possibility of the emergence of resistance to this type of treatment is hard to predict since almost nothing is known about the mechanisms by which Gallium is internalized and affects the physiology of bacterial cells.

In summary, there are significant challenges in front of us regarding the development of efficient and convenient therapeutic approaches to treat and even prevent A. baumannii infections. Such a challenge could be met only by combining multifaceted basic and applied research work focusing on the understanding of basic cellular mechanisms and factors that play key roles in the pathobiology of this bacterium, which has been undervalued for a while as a serious threat to human health.