Co-regulation of biofilm formation and antimicrobial resistance in Acinetobacter baumannii: from mechanisms to therapeutic strategies

Abstract

In recent years, multidrug-resistant Acinetobacter baumannii has emerged globally as a major threat to the healthcare system. It is now listed by the World Health Organization as a priority one for the need of new therapeutic agents. A. baumannii has the capacity to develop robust biofilms on biotic and abiotic surfaces. Biofilm development allows these bacteria to resist various environmental stressors, including antibiotics and lack of nutrients or water, which in turn allows the persistence of A. baumannii in the hospital environment and further outbreaks. Investigation into therapeutic alternatives that will act on both biofilm formation and antimicrobial resistance (AMR) is sorely needed. The aim of the present review is to critically discuss the various mechanisms by which AMR and biofilm formation may be co-regulated in A. baumannii in an attempt to shed light on paths towards novel therapeutic opportunities. After discussing the clinical importance of A. baumannii, this critical review highlights biofilm-formation genes that may be associated with the co-regulation of AMR. Particularly worthy of consideration are genes regulating the quorum sensing system AbaI/AbaR, AbOmpA (OmpA protein), Bap (biofilm-associated protein), the two-component regulatory system BfmRS, the PER-1 β-lactamase, EpsA, and PTK. Finally, this review discusses ongoing experimental therapeutic strategies to fight A. baumannii infections, namely vaccine development, quorum sensing interference, nanoparticles, metal ions, natural products, antimicrobial peptides, and phage therapy. A better understanding of the mechanisms that co-regulate biofilm formation and AMR will help identify new therapeutic targets, as combined approaches may confer synergistic benefits for effective and safer treatments.

Keywords: Acinetobacter baumannii; Antimicrobial resistance; Biofilm; COVID-19; Co-infection; Quorum sensing.

Fig. 1

The five stages in biofilm formation (A) and A. baumannii virulence factors associated with biofilm formation (B). (A) Biofilm formation includes five different stages: (1) initial attachment, when planktonic cells reversibly attach to a surface; (2) irreversible attachment, when bacteria irreversibly attach to a surface and start cell-to-cell adhesion; (3) growth and extracellular polymeric substances (EPS) production, with bacteria starting to produce EPS; (4) biofilm maturation and microcolony formation, when biofilms become fully mature and microcolonies start to appear; and (5) detachment and dispersal, when biofilm bacteria start being released from the biofilm to make biofilms elsewhere. (B) A. baumannii has several virulence factors associated with biofilm formation, including the Csu Pili, which is related to the adhesion of the bacteria to abiotic surfaces such as plastic; AbOmpA, a porin involved in the adhesion of the bacteria to biotic surfaces such as epithelial cells; Bap, a protein involved in the maturation of biofilms and also BfmRS, a regulatory system involved in biofilms formation through the regulation of Csu Pili

Fig. 2

AbaI/AbaR quorum sensing system in A. baumannii. In this system, S-adenosyl methionine (SAM) and acyl-acyl carrier protein substrates (Acyl ACP) are the essential components for the production of AHLs. AbaI-regulated AHLs are released into the extracellular environment. Then, AHLs bind to the receptor AbaR present in the other cells, triggering a cascade of reactions that culminates in the control of expression of several target genes, including genes involved in biofilm formation and also for the production of more AHLs