Tackling antibiotic resistance by inducing transient and robust collateral sensitivity

Hernando-Amado, Sara; Laborda, Pablo; Martínez, José Luis

doi:10.1038/s41467-023-37357-4

Cited by 18 publications

(18 citation statements)

References 80 publications

(177 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It remains unclear whether this difference is specific to cystic fibrosis or whether there are other contexts in which efflux pump mutants survive in the host. To address scenarios in which efflux pump upregulation does prove to be prevalent, it will be interesting to explore the potential benefits of antibiotic cycling or combinations as a means to exploit these mutants’ collateral sensitivity to other antibiotics 63 , 64 .…”

Section: Discussionmentioning

confidence: 99%

A folate inhibitor exploits metabolic differences in Pseudomonas aeruginosa for narrow-spectrum targeting

Chain,

Sheehan,

et al. 2024

Nat Microbiol

View full text Add to dashboard Cite

Pseudomonas aeruginosa is a leading cause of hospital-acquired infections for which the development of antibiotics is urgently needed. Unlike most enteric bacteria, P. aeruginosa lacks enzymes required to scavenge exogenous thymine. An appealing strategy to selectively target P. aeruginosa is to disrupt thymidine synthesis while providing exogenous thymine. However, known antibiotics that perturb thymidine synthesis are largely inactive against P. aeruginosa.Here we characterize fluorofolin, a dihydrofolate reductase (DHFR) inhibitor derived from Irresistin-16, that exhibits significant activity against P. aeruginosa in culture and in a mouse thigh infection model. Fluorofolin is active against a wide range of clinical P. aeruginosa isolates resistant to known antibiotics. Metabolomics and in vitro assays using purified folA confirm that fluorofolin inhibits P. aeruginosa DHFR. Importantly, in the presence of thymine supplementation, fluorofolin activity is selective for P. aeruginosa. Resistance to fluorofolin can emerge through overexpression of the efflux pumps MexCD-OprJ and MexEF-OprN, but these mutants also decrease pathogenesis. Our findings demonstrate how understanding species-specific genetic differences can enable selective targeting of important pathogens while revealing trade-offs between resistance and pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

A folate inhibitor exploits metabolic differences in Pseudomonas aeruginosa for narrow-spectrum targeting

Chain,

Sheehan,

et al. 2024

Nat Microbiol

View full text Add to dashboard Cite

show abstract

“…In clinical isolates, TFR mutations lead to the de-repression of their targets ( 27 ), some of which are efflux transporters, thus contributing to AMR and adjusting to changing environments ( 28 ). NfxB mutants are commonly found in ciprofloxacin-resistant P. aeruginosa clinical strains ( 29 , 30 ). Previous structural studies on several TFRs have revealed that the arginine residue in the HTH domain is in direct contact with the DNA phosphate backbone ( 31 ).…”

Section: Discussionmentioning

confidence: 99%

Promoter regulatory mode evolution enhances the high multidrug resistance of tmexCD1-toprJ1

Wang,

Yang,

et al. 2024

mBio

View full text Add to dashboard Cite

Antibiotic resistance could rapidly emerge from acquiring the mobile antibiotic resistance genes, which are commonly evolved from an intrinsic gene. The emergence of the plasmid-borne mobilized efflux pump gene cluster tmexCD1-toprJ1 renders the last-resort antibiotic tigecycline ineffective, although its evolutionary mechanism remains unclear. In this study, we investigate the regulatory mechanisms of the progenitor NfxB-MexCD-OprJ, a chromosomally encoded operon that does not mediate antibiotic resistance in the wild-type version, and its homologs, TNfxB1-TMexCD1-TOprJ1 mediating high-level tigecycline resistance, and TNfxB3-TMexCD3-TOprJ1. Mechanistic studies demonstrated that in nfxB-mexCD-oprJ , MexCD expression was under a weaker promoter, P mexC and inhibited by a strong repressor NfxB. For tmexCD1-toprJ1 , TMexCD1 was highly expressed owing to the presence of a strong promoter, P tmexC1 , and an inactive suppressor, TNfxB1, with a T39R mutation that rendered it unable to bind to promoter DNA. In tnfxB3-tmexCD3-toprJ1b , TMexCD3 expression was intermediate because of the local regulator TNfxB3, which binds to two inverted repeat sequences of P tmexC . Additionally, TNfxB3 exhibited lower protein expression and weaker DNA binding affinity than its ancestor NfxB, together with their promoter activities difference explaining the different expression levels of tmexCD-toprJ homologs. Distinct fitness burdens on these homologs-carrying bacteria were observed due to the corresponding expression level, which might be associated with their global prevalence. In summary, our data depict the mechanisms underlying the evolution and dissemination of an important mobile antibiotic resistance gene from an intrinsic chromosomal gene. IMPORTANCE As antibiotic resistance seriously challenges global health, tigecycline is one of the few effective drugs in the pipeline against infections caused by multidrug-resistant pathogens. Our previous work identified a novel tigecycline resistance efflux pump gene cluster tmexCD1-toprJ1 in animals and humans, together with its various variants, a rising clinical concern. Herein, this study focused on how the local regulation modes of tmexCD1-toprJ1 evolved to a highly expressed efflux pump. Through comparative analysis between three tnfxB-tmexCD-toprJ homologs and their progenitor nfxB-mexCD-oprJ , modes, we demonstrated the evolutionary dynamics from a chromosomal silent gene to an active state. We found the de-repression of the local regulator and an increase of the promoter activity work together to promote a high production of drug efflux machines and enhance multidrug resistance. Our findings revealed that TMexCD1-TOprJ1 adopts a distinct evolutionary path to achieve higher multidrug resistance, urgently needing tight surveillance.

show abstract

“…For P. aeruginosa biofilms, a final inoculum of 1 × 10 4 colony-forming units (cfu) mL –1 was added to the polycarbonate disk and incubated statically for 24 h at 37 °C before treatment. , For polymicrobial biofilms, a final inoculum of 1 × 10 5 cfu mL –1 for C. albicans and 1 × 10 6 cfu mL –1 for S.…”

Section: Methodsmentioning

confidence: 99%

Ciprofloxacin Poly(β-amino ester) Conjugates Enhance Antibiofilm Activity and Slow the Development of Resistance

Kasza,

Richards,

Jones

et al. 2024

ACS Appl. Mater. Interfaces

View full text Add to dashboard Cite

To tackle the emerging antibiotic resistance crisis, novel antimicrobial approaches are urgently needed. Bacterial biofilms are a particular concern in this context as they are responsible for over 80% of bacterial infections and are inherently more recalcitrant toward antimicrobial treatments. The high tolerance of biofilms to conventional antibiotics has been attributed to several factors, including reduced drug diffusion through the dense exopolymeric matrix and the upregulation of antimicrobial resistance machinery with successful biofilm eradication requiring prolonged high doses of multidrug treatments. A promising approach to tackle bacterial infections involves the use of polymer drug conjugates, shown to improve upon free drug toxicity and bioavailability, enhance drug penetration through the thick biofilm matrix, and evade common resistance mechanisms. In the following study, we conjugated the antibiotic ciprofloxacin (CIP) to a small library of biodegradable and biocompatible poly(β-amino ester) (PBAE) polymers with varying central amine functionality. The suitability of the polymers as antibiotic conjugates was then verified in a series of assays including testing of efficacy and resistance response in planktonic Gram-positive and Gram-negative bacteria and the reduction of viability in mono-and multispecies biofilm models. The most active polymer within the prepared PBAE-CIP library was shown to achieve an over 2-fold increase in the reduction of biofilm viability in a Pseudomonas aeruginosa monospecies biofilm and superior elimination of all the species present within the multispecies biofilm model. Hence, we demonstrate that CIP conjugation to PBAEs can be employed to achieve improved antibiotic efficacy against clinically relevant biofilm models.

show abstract

Tackling antibiotic resistance by inducing transient and robust collateral sensitivity

Cited by 18 publications

References 80 publications

A folate inhibitor exploits metabolic differences in Pseudomonas aeruginosa for narrow-spectrum targeting

A folate inhibitor exploits metabolic differences in Pseudomonas aeruginosa for narrow-spectrum targeting

Promoter regulatory mode evolution enhances the high multidrug resistance of tmexCD1-toprJ1

Ciprofloxacin Poly(β-amino ester) Conjugates Enhance Antibiofilm Activity and Slow the Development of Resistance

Contact Info

Product

Resources

About