Bacterial Persisters and Infection: Past, Present, and Progressing

Gollan, Bridget; Grabe, Grzegorz; Michaux, Charlotte; Hélaine, Sophie

doi:10.1146/annurev-micro-020518-115650

Cited by 194 publications

(202 citation statements)

References 129 publications

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“…Bacterial persisters were first identified in 1944 by Joseph Bigger, who found that a small portion of Staphylococcus population was not killed by penicillin but still kept the susceptibility to the same antibiotic after re-growth [1]. Although bacterial persistence has been noticed for seven decades, it was appreciated only recently as one of the major causes of antibiotic recalcitrance and relapse of infection diseases [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Non-walled spherical Acinetobacter baumannii is an important type of persister upon β -lactam antibiotic treatment

Zou¹,

Kou²,

Xie³

et al. 2020

Emerging Microbes & Infections

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Bacterial persistence is one of the major causes of antibiotic treatment failure and the step stone for antibiotic resistance. However, the mechanism by which persisters arise has not been well understood. Maintaining a dormant state to prevent antibiotics from taking effect is believed to be the fundamental mechanistic basis, and persisters normally maintain an intact cellular structure. Here we examined the morphologies of persisters in Acinetobacter baumannii survived from the treatment by three major classes of antibiotics (i.e. β-lactam, aminoglycoside, and fluoroquinolone) with microcopy and found that a fraction of enlarged spherical bacteria constitutes a major sub-population of bacterial survivors from β-lactam antibiotic treatment, whereas survivors from the treatment of aminoglycoside and fluoroquinolone were less changed morphologically. Further studies showed that these spherical bacteria had completely lost their cell wall structures but could survive without any osmoprotective reagent. The spherical bacteria were not the viable-but-nonculturable cells and they could revive upon the removal of β-lactam antibiotics. Importantly, these non-walled spherical bacteria also persisted during antibiotic therapy in vivo using Galleria mellonella as the infection model. Additionally, the combinational treatment on A. baumannii by β-lactam and membrane-targeting antibiotic significantly enhanced the killing efficacy. Our results indicate that in addition to the dormant, structure intact persisters, the non-wall spherical bacterium is another important type of persister in A. baumannii. The finding suggests that targeting the bacterial cell membrane during β-lactam chemotherapy could enhance therapeutic efficacy on A. baumannii infection, which might also help to reduce the resistance development of A. baumannii.

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Section: Introductionmentioning

confidence: 99%

Non-walled spherical Acinetobacter baumannii is an important type of persister upon β -lactam antibiotic treatment

Zou¹,

Kou²,

Xie³

et al. 2020

Emerging Microbes & Infections

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“…The underlying mechanisms, however, await further investigation. Bacteria, especially in biofilms, can develop persistent cells that are highly resistant to host immune attack, various environment stress and antibiotics [40][41][42][43][44]. Based on the results of the regrowth experiment of cells in the 10 −7 dilution of the 2.0, 1.0 and 0.50 µg/mL groups (Figure 7), we deduced that the lower the concentration of azalomycin F 5a used to treat S. aureus biofilms, the greater the proportion of persistent cells there would be.…”

Section: Discussionmentioning

confidence: 99%

Azalomycin F5a Eradicates Staphylococcus aureus Biofilm by Rapidly Penetrating and Subsequently Inducing Cell Lysis

Yuan

et al. 2020

IJMS

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Antimicrobial resistance has emerged as a serious threat to public health. Bacterial biofilm, as a natural lifestyle, is a major contributor to resistance to antimicrobials. Azalomycin F5a, a natural guanidine-containing polyhydroxy macrolide, has remarkable activities against Gram-positive bacteria, including Staphylococcus aureus, a major causative agent of hospital-acquired infections. To further evaluate its potential to be developed as a new antimicrobial agent, its influence on S. aureus biofilm formation was evaluated using the crystal violet method, and then its eradication effect against mature biofilms was determined by confocal laser scanning microscopy, the drop plate method, and regrowth experiments. The results showed that azalomycin F5a could significantly inhibit S. aureus biofilm formation, and such effects were concentration dependent. In addition, it can also eradicate S. aureus mature biofilms with the minimum biofilm eradication concentration of 32.0 μg/mL. As extracellular deoxyribonucleic acid (eDNA) plays important roles in the structural integrity of bacterial biofilm, its influence on the eDNA release in S. aureus biofilm was further analyzed using gel electrophoresis. Combined with our previous works, these results indicate that azalomycin F5a could rapidly penetrate biofilm and causes damages to the cell membrane, leading to an increase in DNase release and eventually eradicating S. aureus biofilm.

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“…Using just one antibody against one target, when bacteria secrete or have more than 200-400+ targets on their surface with presumed roles in virulence, may not be sufficient. Further, most approaches do not take into account that bacteria have different lifestyles, and therefore variable surface or secreted protein expression profiles, while residing within the host: vegetative, encapsulated or unencapsulated, biofilm associated, and intracellular, among others [46][47][48][49]. Finally, with respect to the mAb KB-001A, a diagnostic assay was not being used to properly identify patients with P. aeruginosa at the outset of the study.…”

Section: Previous Failures Lead To Current Successmentioning

confidence: 99%

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

2020

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In the beginning of the 21st century, the frequency of antimicrobial resistance (AMR) has reached an apex, where even 4th and 5th generation antibiotics are becoming useless in clinical settings. In turn, patients are suffering from once-curable infections, with increases in morbidity and mortality. The root cause of many of these infections are the ESKAPEE pathogens (Enterococcus species, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli), which thrive in the nosocomial environment and are the bacterial species that have seen the largest rise in the acquisition of antibiotic resistance genes. While traditional small-molecule development still dominates the antibacterial landscape for solutions to AMR, some researchers are now turning to biological approaches as potential game changers. Monoclonal antibodies (mAbs)—more specifically, human monoclonal antibodies (Hu-mAbs)—have been highly pursued in the anti-cancer, autoimmune, and antiviral fields with many success stories, but antibody development for bacterial infection is still just scratching the surface. The untapped potential for Hu-mAbs to be used as a prophylactic or therapeutic treatment for bacterial infection is exciting, as these biologics do not have the same toxicity hurdles of small molecules, could have less resistance as they often target virulence proteins rather than proteins required for survival, and are narrow spectrum (targeting just one pathogenic species), therefore avoiding the disruption of the microbiome. This mini-review will highlight the current antibacterial mAbs approved for patient use, the success stories for mAb development, and new Hu-mAb products in the antibacterial pipeline.

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Bacterial Persisters and Infection: Past, Present, and Progressing

Cited by 194 publications

References 129 publications

Non-walled spherical Acinetobacter baumannii is an important type of persister upon β -lactam antibiotic treatment

Non-walled spherical Acinetobacter baumannii is an important type of persister upon β -lactam antibiotic treatment

Azalomycin F5a Eradicates Staphylococcus aureus Biofilm by Rapidly Penetrating and Subsequently Inducing Cell Lysis

Monoclonal Antibodies as an Antibacterial Approach Against Bacterial Pathogens

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