Convergence of Biofilm Formation and Antibiotic Resistance in Acinetobacter baumannii Infection

Abstract

Acinetobacter baumannii (A. baumannii) is a leading cause of nosocomial infections as this pathogen has certain attributes that facilitate the subversion of natural defenses of the human body. A. baumannii acquires antibiotic resistance determinants easily and can thrive on both biotic and abiotic surfaces. Different resistance mechanisms or determinants, both transmissible and non-transmissible, have aided in this victory over antibiotics. In addition, the propensity to form biofilms (communities of organism attached to a surface) allows the organism to persist in hospitals on various medical surfaces (cardiac valves, artificial joints, catheters, endotracheal tubes, and ventilators) and also evade antibiotics simply by shielding the bacteria and increasing its ability to acquire foreign genetic material through lateral gene transfer. The biofilm formation rate in A. baumannii is higher than in other species. Recent research has shown how A. baumannii biofilm-forming capacity exerts its effect on resistance phenotypes, development of resistome, and dissemination of resistance genes within biofilms by conjugation or transformation, thereby making biofilm a hotspot for genetic exchange. Various genes control the formation of A. baumannii biofilms and a beneficial relationship between biofilm formation and "antimicrobial resistance" (AMR) exists in the organism. This review discusses these various attributes of the organism that act independently or synergistically to cause hospital infections. Evolution of AMR in A. baumannii, resistance mechanisms including both transmissible (hydrolyzing enzymes) and non-transmissible (efflux pumps and chromosomal mutations) are presented. Intrinsic factors [biofilm-associated protein, outer membrane protein A, chaperon-usher pilus, iron uptake mechanism, poly-β-(1, 6)-N-acetyl glucosamine, BfmS/BfmR two-component system, PER-1, quorum sensing] involved in biofilm production, extrinsic factors (surface property, growth temperature, growth medium) associated with the process, the impact of biofilms on high antimicrobial tolerance and regulation of the process, gene transfer within the biofilm, are elaborated. The infections associated with colonization of A. baumannii on medical devices are discussed. Each important device-related infection is dealt with and both adult and pediatric studies are separately mentioned. Furthermore, the strategies of preventing A. baumannii biofilms with antibiotic combinations, quorum sensing quenchers, natural products, efflux pump inhibitors, antimicrobial peptides, nanoparticles, and phage therapy are enumerated.

Keywords: Acinetobacter baumannii; adult; antimicrobial resistance; biofilm prevention; biofilm regulation; biofilm-associated infections; paediatric.

Figure 1

Evolution of antimicrobial resistance among Acinetobacter baumannii: Top portion of the diagram shows the year of the first report of antimicrobial resistance in A. baumannii; the lower portion shows the year of introduction of antimicrobials (approximate year) in the market where colored lines indicate different antimicrobial groups.

Figure 2

Schematic diagram of different antimicrobial resistance mechanisms in A. baumannii: (1) increased expression of efflux pumps that expel out antibiotics from the bacterial cell; (2) reduced expression of porin or porin loss results in the decreased antibiotic entry; (3) β-lactamases cause enzymatic inactivation of antibiotics; (4) aminoglycoside modifying enzymes decrease the affinity of aminoglycoside antibiotics for ribosomal subunit or methylation of 30S rRNA decrease the binding of aminoglycosides; (5) mutations in topoisomerase IV and DNA gyrase decrease the binding of fluoroquinolones; (6) modification of penicillin-binding-proteins (PBPs) prevent the bindings of β-lactams; (7) modification of lipopolysaccharides (LPS) cause decreased binding of colistin; (8) presence of capsular polysaccharide acts as a barrier against environmental stress, anti-phagocytic effect, etc.; (9) ability to form biofilm cause high antimicrobial resistance.

Figure 3

A schematic diagram representing the intrinsic factors (genes) and the extrinsic factors that regulate biofilm formation in A. baumannii: OM, Outer membrane; IM, Inner membrane. Intrinsic factors: PNAG, Poly-(1–6)-N-acetylglucosamine; Csu, Chaperon/usher pilus system; OmpA, Outer membrane protein A; bla_PER− 1, Beta-lactamase PER-1; bap-Ab, A. baumannii biofilm-associated protein; AHLs, N-acyl homoserine lactones; Extrinsic factors: surface properties, growth temperature, and growth medium.

Figure 4

Diagrammatic representation of the antibiotic resistance mechanisms of biofilm-embedded bacterial cells: The biofilm is attached to a biotic or abiotic surface (brown rectangle). Development of persister cells (dark green) and less active deep layer cells (light green) in the stress zone (the core of the biofilm, light cream color) where fewer nutrients are available. The various resistant mechanisms depicted in the figure are as follows: (1) matrix exopolysaccharides cause slow penetration of antibiotics; (2) extracellular DNA (eDNA); (3) multidrug efflux pumps; (4) outer membrane protein; (5) antibiotic degrading enzymes and target modifications (6) quorum sensing; (7) stress responses (oxidative stress response, stringent response, etc.); (8) toxin-antitoxin system and (9) SOS responses.

Figure 5

Diagrammatic representation of the strategies to tackle antibiotic-resistant biofilm communities: antibiotic treatment, quorum sensing inhibitors, natural products/essential oils, antimicrobials peptides, efflux pump inhibitors, nanoparticles, and phage therapy.