Relationship between biofilm formation and antibiotic resistance of Klebsiella pneumoniae and updates on antibiofilm therapeutic strategies

Bacteria belonging to the genus Klebsiella frequently cause human nosocomial infections. In particular, the medically most important Klebsiella species, Klebsiella pneumoniae, accounts for a significant proportion of hospital-acquired urinary tract infections, pneumonia, septicemias, and soft tissue infections. The principal pathogenic reservoirs for transmission of Klebsiella are the gastrointestinal tract and the hands of hospital personnel. Because of their ability to spread rapidly in the hospital environment, these bacteria tend to cause nosocomial outbreaks. Hospital outbreaks of multidrug-resistant Klebsiella spp., especially those in neonatal wards, are often caused by new types of strains, the so-called extended-spectrum-β-lactamase (ESBL) producers. The incidence of ESBL-producing strains among clinical Klebsiella isolates has been steadily increasing over the past years. The resulting limitations on the therapeutic options demand new measures for the management of Klebsiella hospital infections. While the different typing methods are useful epidemiological tools for infection control, recent findings about Klebsiella virulence factors have provided new insights into the pathogenic strategies of these bacteria. Klebsiella pathogenicity factors such as capsules or lipopolysaccharides are presently considered to be promising candidates for vaccination efforts that may serve as immunological infection control measures.

Metal-based nanoparticles have been extensively investigated for a set of biomedical applications. According to the World Health Organization, in addition to their reduced size and selectivity for bacteria, metal-based nanoparticles have also proved to be effective against pathogens listed as a priority. Metal-based nanoparticles are known to have non-specific bacterial toxicity mechanisms (they do not bind to a specific receptor in the bacterial cell) which not only makes the development of resistance by bacteria difficult, but also broadens the spectrum of antibacterial activity. As a result, a large majority of metal-based nanoparticles efficacy studies performed so far have shown promising results in both Gram-positive and Gram-negative bacteria. The aim of this review has been a comprehensive discussion of the state of the art on the use of the most relevant types of metal nanoparticles employed as antimicrobial agents. A special emphasis to silver nanoparticles is given, while others (e.g., gold, zinc oxide, copper, and copper oxide nanoparticles) commonly used in antibiotherapy are also reviewed. The novelty of this review relies on the comparative discussion of the different types of metal nanoparticles, their production methods, physicochemical characterization, and pharmacokinetics together with the toxicological risk encountered with the use of different types of nanoparticles as antimicrobial agents. Their added-value in the development of alternative, more effective antibiotics against multi-resistant Gram-negative bacteria has been highlighted.

The global emergence of multidrug-resistant Gram-negative bacteria is a growing threat to antibiotic therapy. The chromosomally encoded drug efflux mechanisms that are ubiquitous in these bacteria greatly contribute to antibiotic resistance and present a major challenge for antibiotic development. Multidrug pumps, particularly those represented by the clinically relevant AcrAB-TolC and Mex pumps of the resistance-nodulation-division (RND) superfamily, not only mediate intrinsic and acquired multidrug resistance (MDR) but also are involved in other functions, including the bacterial stress response and pathogenicity. Additionally, efflux pumps interact synergistically with other resistance mechanisms (e.g., with the outer membrane permeability barrier) to increase resistance levels. Since the discovery of RND pumps in the early 1990s, remarkable scientific and technological advances have allowed for an in-depth understanding of the structural and biochemical basis, substrate profiles, molecular regulation, and inhibition of MDR pumps. However, the development of clinically useful efflux pump inhibitors and/or new antibiotics that can bypass pump effects continues to be a challenge. Plasmid-borne efflux pump genes (including those for RND pumps) have increasingly been identified. This article highlights the recent progress obtained for organisms of clinical significance, together with methodological considerations for the characterization of MDR pumps. Copyright © 2015, American Society for Microbiology. All Rights Reserved.