PBP Target Profiling by β-Lactam and β-Lactamase Inhibitors in Intact Pseudomonas aeruginosa: Effects of the Intrinsic and Acquired Resistance Determinants on the Periplasmic Drug Availability

Montaner, María; López-Argüello, Silvia; Oliver, Antonio; Moyá, Bartolomé

doi:10.1128/spectrum.03038-22

Cited by 7 publications

(13 citation statements)

References 46 publications

(71 reference statements)

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“…However, the number of colistin-resistant (COL-R) bacteria is also increasing. The appearance of COL-R GNB has been frequently reported, signifying the failure of the last-resort agents to defeat drug-resistant GNB. , New antimicrobial agents to deal with this situation are urgently needed at this time. , …”

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confidence: 99%

“…2,3 Based on their resistance characteristics toward antibiotics in the course of clinical treatment, drug-resistant pathogens are classified as multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR) bacteria. 4,5 A pathogen that is nonsusceptible to at least one agent in three or more antimicrobial categories is considered MDR. A pathogen that is nonsusceptible to at least one agent in all but two or fewer categories is considered XDR, whereas a PDR bacterium exhibits resistance to all of the tested clinical antibiotics.…”

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confidence: 99%

“…However, some public health concerns have also gradually emerged. One of these acute problems is the emergence and rise of drug-resistant bacteria, especially Gram-negative bacteria (GNB), in clinical treatment due to the overuse of antibiotics during recent decades, which cannot be easily ignored. , Based on their resistance characteristics toward antibiotics in the course of clinical treatment, drug-resistant pathogens are classified as multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR) bacteria. , A pathogen that is nonsusceptible to at least one agent in three or more antimicrobial categories is considered MDR. A pathogen that is nonsusceptible to at least one agent in all but two or fewer categories is considered XDR, whereas a PDR bacterium exhibits resistance to all of the tested clinical antibiotics …”

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confidence: 99%

“…For instance, lower respiratory tract infections caused by MDR/XDR account for more than 1.5 million resistance-associated deaths, making it the most burdensome infectious syndrome. , PDR Acinetobacter baumannii was found to be the most crucial causal agent of diseases such as pneumonia, bacteremia, meningitis, and soft tissue and urinary tract infections . Undoubtedly, new antimicrobial agents need to be urgently explored to handle this serious situation. , …”

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confidence: 99%

“…8 Undoubtedly, new antimicrobial agents need to be urgently explored to handle this serious situation. 4,5 For about two decades, colistin (COL) has been used to treat infectious diseases caused by MDR and carbapenemresistant GNB in 1950. 9 Although the reported nephrotoxicity and neurotoxicity led to a gradual decrease in its use, 10 it was recently reused as a salvage antimicrobial agent against bacteria resistant to all other antibiotic classes in recent years.…”

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confidence: 99%

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Bithionol Restores Sensitivity of Multidrug-Resistant Gram-Negative Bacteria to Colistin with Antimicrobial and Anti-biofilm Effects

et al. 2023

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Being among the few last-resort antibiotics, colistin (COL) has been used to treat severe infectious diseases, such as those caused by multidrugresistant Gram-negative bacteria (MDR GNB). However, the appearance of colistin-resistant (COL-R) GNB has been frequently reported. Therefore, novel antimicrobial strategies need to be urgently sought to address this resistance challenge. In the present study, antimicrobial drug screening conducted revealed that bithionol (BT), approved by the Food and Drug Administration and used as an anthelminthic drug for paragonimiasis, exhibited a synergistic antibacterial effect with COL. Clinically isolated COL-R GNB were used as candidates to evaluate the synergistic antibacterial activity. The results revealed that BT could significantly reverse the sensitivity of COL-R GNB to COL. Furthermore, the combined application of BT and COL can reduce bacterial biofilm formation and have a scavenging effect on the mature biofilm in vitro. The damage caused to the bacterial cell membrane integrity by the BT/COL combination was observed under a fluorescence microscope. The fluorescence intensity of reactive oxygen species also increased in the experimental group. The BT/COL combination also exhibited a synergistic antibacterial effect in vivo. Importantly, BT was confirmed to be safe at the highest concentrations that exerted synergistic effects on all tested strains. In conclusion, our findings demonstrated that BT exerted synergistic antimicrobial and anti-biofilm effects when combined with COL against MDR organisms, especially COL-R GNB, in vitro and in vivo. The findings thus provide a reference for the clinical response to the serious challenge of MDR GNB and the exploitation of the potential antibacterial activities of existing clinical non-antibacterial drugs.

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confidence: 99%

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Bithionol Restores Sensitivity of Multidrug-Resistant Gram-Negative Bacteria to Colistin with Antimicrobial and Anti-biofilm Effects

et al. 2023

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Temperate phage-antibiotic synergy is widespread, but varies by phage, host, and antibiotic pairing

Fatima,

Hynes

2024

Preprint

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With a decline in antibiotic effectiveness, there is a renewed interest in bacteriophage (phage) therapy. Phages are bacterial-specific viruses that can be used alone or with antibiotics to reduce bacterial load. Most phages are unsuitable for therapy because they are ‘temperate’ and can integrate into the host genome, forming a lysogen which is protected from subsequent phage infections. However, integrated phages can be awakened by stressors such as antibiotics. This interaction was previously reported to result in a potent synergy between antibiotic classes and a modelE. colitemperate phage, which can readily eradicate the bacterium at sub-lethal concentrations of antibiotics, despite the poor effectiveness of the phage alone. Here we explore the generalizability of this synergy to a clinically relevant pathogen:Pseudomonas aeruginosa. Thirty-six temperate phages isolated from clinical strains were screened for synergy with six antibiotics (ciprofloxacin, levofloxacin, meropenem, piperacillin, tobramycin, polymyxin B), using checkerboard assays. Interestingly, our screen identified phages that can synergize with each antibiotic, despite their widely differing targets - however, these are highly phage-antibiotic and phage-host pairing specific. Screening the strongest pairings across multiple clinical strains reveal that these phages can reduce the antibiotic minimum inhibitory concentration up to 32-fold, even in a resistant isolate, functionally re-sensitizing the bacterium to the antibiotic. When meropenem and tobramycin were effective synergistic agents, they did not reduce the frequency of lysogens, suggesting a mechanism of action independent of the temperate nature of the phages. In contrast, ciprofloxacin and piperacillin were able to reduce the frequency of lysogeny, the former by inducing phages – as previously reported inE. coli. Curiously, synergy with piperacillin reduced the frequency of lysogeny, but not by inducing the phages, and therefore likely acts by biasing the phage away from lysogeny in the initial infection. Overall, our findings indicate that temperate phages can act as adjuvants to antibiotics in clinically relevant pathogens, even in the presence of antibiotic resistance, thereby drastically expanding their therapeutic potential.

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Temperate phage-antibiotic synergy across antibiotic classes reveals new mechanism for preventing lysogeny

Al-Anany,

Fatima,

Nair

et al. 2024

mBio

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A recent demonstration of synergy between a temperate phage and the antibiotic ciprofloxacin suggested a scalable approach to exploiting temperate phages in therapy, termed temperate phage-antibiotic synergy, which specifically interacted with the lysis-lysogeny decision. To determine whether this would hold true across antibiotics, we challenged Escherichia coli with the phage HK97 and a set of 13 antibiotics spanning seven classes. As expected, given the conserved induction pathway, we observed synergy with classes of drugs known to induce an SOS response: a sulfa drug, other quinolones, and mitomycin C. While some β-lactams exhibited synergy, this appeared to be traditional phage-antibiotic synergy, with no effect on the lysis-lysogeny decision. Curiously, we observed a potent synergy with antibiotics not known to induce the SOS response: protein synthesis inhibitors gentamicin, kanamycin, tetracycline, and azithromycin. The synergy results in an eightfold reduction in the effective minimum inhibitory concentration of gentamicin, complete eradication of the bacteria, and, when administered at sub-optimal doses, drastically decreases the frequency of lysogens emerging from the combined challenge. However, lysogens exhibit no increased sensitivity to the antibiotic; synergy was maintained in the absence of RecA; and the antibiotic reduced the initial frequency of lysogeny rather than selecting against formed lysogens. Our results confirm that SOS-inducing antibiotics broadly result in temperate-phage-specific synergy, but that other antibiotics can interact with temperate phages specifically and result in synergy. This is the first report of a means of chemically blocking entry into lysogeny, providing a new means for manipulating the key lysis-lysogeny decision. IMPORTANCE The lysis-lysogeny decision is made by most bacterial viruses (bacteriophages, phages), determining whether to kill their host or go dormant within it. With over half of the bacteria containing phages waiting to wake, this is one of the most important behaviors in all of biology. These phages are also considered unusable for therapy because of this behavior. In this paper, we show that many antibiotics bias this behavior to “wake” the dormant phages, forcing them to kill their host, but some also prevent dormancy in the first place. These will be important tools to study this critical decision point and may enable the therapeutic use of these phages.

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PBP Target Profiling by β-Lactam and β-Lactamase Inhibitors in Intact Pseudomonas aeruginosa: Effects of the Intrinsic and Acquired Resistance Determinants on the Periplasmic Drug Availability

Cited by 7 publications

References 46 publications

Bithionol Restores Sensitivity of Multidrug-Resistant Gram-Negative Bacteria to Colistin with Antimicrobial and Anti-biofilm Effects

Bithionol Restores Sensitivity of Multidrug-Resistant Gram-Negative Bacteria to Colistin with Antimicrobial and Anti-biofilm Effects

Temperate phage-antibiotic synergy is widespread, but varies by phage, host, and antibiotic pairing

Temperate phage-antibiotic synergy across antibiotic classes reveals new mechanism for preventing lysogeny

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