Phage Abp1 Rescues Human Cells and Mice from Infection by Pan-Drug Resistant Acinetobacter Baumannii

Abstract

Background/Aims: As an “ESKAPE” pathogen, Acinetobacter baumannii is one of the leading causes of drug-resistant infections in humans. Phage therapy may be a useful strategy in treating infections caused by drug-resistant A. baumannii. Among 21 phage strains that were isolated and described earlier, we investigated the therapeutic efficacy of Abp1 because of its relatively wide host range. Methods: Phage stability assays were used to evaluate thermal and pH stability of Abp1. Abp1 was co-cultured with A. baumannii (AB1) over a range of multiplicities of infection to determine its bactericidal efficacy. HeLa or THP-1 cells were used in the cytotoxicity and protection assays. Finally, the therapeutic effects of Abp1 on local and systemic A. baumannii infection in mice were determined. Results: We found that Abp1 exhibits high thermal and pH stability and has a low frequency of lysogeny. Bacteriophage resistance also occurs at a very low frequency (3.51±0.46×10^-8), and Abp1 can lyse almost all host cells at a MOI as low as 0.1. Abp1 has no detectable cytotoxicity to HeLa or THP-1 cells as determined by LDH release assay. Abp1 can rescue HeLa cells from A. baumannii infection, even if introduced 2 hours post infection. In both local and systemic A. baumannii infection mouse models, Abp1 treatment exhibits good therapeutic effects. Conclusion: Abp1 is an excellent candidate for phage therapy against drug-resistant A. baumannii infections.

<p>How Phages Overcome the Challenges of Drug Resistant Bacteria in Clinical Infections</p>

“…Use of bacteriophage in recent insightful research, against MDR, XDR, and PDR bacteria, might be relevant to therapies against S. aureus, P. aeruginosa, A. baumannii, and infectious diseases. 18,31 Why Would We Need Phage Therapy?…”

“…They have special characteristics, such as bactericidal effect, low inherent toxicity, high selectivity, lack of cross-resistance with antibiotic classes as well as self-multiplication in the presence of the bacterial host that distinguish them from conventional antibiotics. 18,27,33,[35][36][37] Also, unlike broad-spectrum antibiotics, phage spare the commensal microbiota due to their strain-specific activity, which is particularly important for malnourished and immunodeficient people. Eventually, they can be prepared in dry powder formulations that do not require a cold chain.…”

“…Another advantage of phages is the absence of cross-resistance to antibiotics and mechanisms developed by bacteria to resist antibiotics that prevent interference with phage efficacy, therefore phages are considered as an effective solution against MDR, XDR, and PDR bacteria. 18,27,45 When a bacterium develops resistance to a particular phage, it will remain sensitive to phages with different cell surface receptors, such as receptors specific to lipopolysaccharides, proteins, teichoic acids. 46 So, using a cocktail of phages has some advantages such as the higher impact on targeted bacteria and a lower probability of development of phage-resistant bacteria due to the presence of different types of phages infecting the same species and strains.…”

“…In A. baumannii infection in mice, Abp1 therapy, either local or systemic, displays good therapeutic effects. 18 Myoviridae bacteriophage vB_AbaM_IME200 against PDR A. baumannii was tested by Bai et al The results demonstrated that phage and its depolymerase had strong lytic activity against PDR A. baumannii. 106 Furthermore, the combined use of phages and antibiotics has shown better effects than antibiotic therapy alone, against biofilm and drug resistant bacteria such as Burkholderia cepacia, P. aeruginosa, E. coli, Klebsiella pneumoniae, E. faecalis, A. baumannii, S. pneumoniae, and S. aureus in multiple studies.…”

“…14 In the last decade, supporting evidence is provided worldwide to help establish the efficacy of bacteriophages in combatting the challenges posed by MDR, XDR, and PDR bacteria, and even show the ability of bacteriophages to replace antibiotic treatments. [15][16][17][18] This review focuses on the challenges in the conventional treatment of MDR, XDR, and PDR bacteria and the mechanisms by which phages may help to treat such infections. The most recent studies on the potential of phages, phage cocktails, and the enzymes of lytic phages in fighting these resistant bacteria are included in this review.…”