Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.04.22.649919

Synergistic cefiderocol-containing antibiotic combinations active against highly drug-resistant Acinetobacter baumannii patient isolates with diverse resistance mechanisms

Halim, J.·Keane, A. P.·Bouzo, J.·Aderibigbe, T.·Chicola, J. A.·Nolan, K. T.·Jonnalgadda, K.·Tran, J. X.·Carabetta, V.
View original source ↗Export metadata ↓

Abstract

Acinetobacter baumannii is a nosocomial pathogen notorious for rapidly acquiring resistance to nearly all antibiotics, including last-line agents. Cefiderocol (FDC) is a novel siderophore cephalosporin antibiotic with in vitro activity against A. baumannii that is now used clinically, but resistance is emerging. There is limited data regarding FDC-containing antibiotic combinations with synergistic activity against A. baumannii, which may increase the potency of the drug and reduce resistance development. In this study, we evaluated the activity of FDC alone and in combination with other antibiotics against 21 extensively drug-resistant (XDR) and pandrug-resistant (PDR) A. baumannii clinical isolates. FDC possesses strong in vitro activity and was highly effective in combination with ceftazidime-avibactam (CAZ-AVI) and sulbactam-durlobactam (SUL-DUR), as well as amikacin, doxycycline, and sulbactam. We also identified several FDC-containing combinations effective against a metallo-{beta}-lactamase (MBL)-producing strain. Previously, we performed whole genome sequencing on selected strains in our collection, allowing for the identification of resistance genes and mechanisms associated with susceptibility patterns and synergy outcomes. These findings highlight promising FDC-based combinations for treating highly drug-resistant A. baumannii infections and provide insight into the genetic basis of FDC resistance and response. Author SummaryAcinetobacter baumannii is a frequent cause of hospital-acquired pneumonia, and bloodstream and wound infections in vulnerable populations, such as those who are critically ill or immunocompromised. Infections caused by A. baumannii are a growing problem in hospitals around the world, especially because of increasing resistance to almost all available antibiotics. Physicians have few treatment options available, which leads to high mortality rates. One newer antibiotic, cefiderocol, has shown promise against these infections, but resistance to this drug is already emerging. In our study, we looked for combinations of cefiderocol with other traditional and newly available antibiotics that work better together than alone. We tested these combinations against over 20 highly drug-resistant strains isolated from patients, including one strain that produces a strong resistance enzyme called NDM-1. We found that pairing cefiderocol with certain drugs, especially ceftazidime-avibactam, sulbactam-durlobactam, amikacin, and doxycycline, often worked significantly better than using cefiderocol alone. These combinations were able to prevent the growth of even the most resistant strains in our collection. Our work highlights new potential treatment options that physicians may use in the future to help patients with these dangerous, life-threatening infections, especially when standard antibiotics are no longer effective.

Source connections

Explore related subjects

microbiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Halim, J., Keane, A. P., Bouzo, J., Aderibigbe, T., Chicola, J. A., Nolan, K. T., Jonnalgadda, K., Tran, J. X., Carabetta, V.. 2025-04-22. Synergistic cefiderocol-containing antibiotic combinations active against highly drug-resistant Acinetobacter baumannii patient isolates with diverse resistance mechanisms. https://doi.org/10.1101/2025.04.22.649919

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Matrix-controlled emergence of biofilm architecture shapes antimicrobial survival

Biofilms are structured microbial communities whose extracellular matrix is widely regarded as a basis of their protection against antimicrobial compounds. Yet how matrix production by individual bacteria gives rise to collective architecture and antimicrobial protection remains poorly understood. Here, we systematically varied expression of the master biofilm regulator csgD in Salmonella enterica and found that increasing matrix production reorganizes biofilms from dense, isotropic packings into sparse, nematically aligned communities by altering cell-cell interactions. By combining experimentally measured biofilm architectures with reaction-diffusion modeling, we show that these structural changes produce distinct patterns of antimicrobial killing, ranging from preferential killing near the liquid-biofilm interface to more uniform killing throughout the community. Consequently, increasing matrix production unexpectedly reduces antimicrobial survival by shifting the biofilm into different transport regimes, while strain-specific physiological differences further modulate antimicrobial depletion. Rather than acting as a passive barrier, EPS therefore shapes antimicrobial susceptibility by reorganizing biofilm architecture and its transport properties. EPS thus provides a physical link between molecular regulation, collective architecture and antimicrobial survival, providing a quantitative framework for understanding how cellular matrix production generates emergent biofilm function.

microbiology↗
bioRxiv2026

Mapping virulence-associated protein interaction networks reveals regulators of thermotolerance in Cryptococcus neoformans

Protein-protein interactions (PPIs) influence critical biological processes in pathogenic microorganisms, such as the human fungal pathogen, Cryptococcus neoformans. Fungal thermotolerance and stress response pathways are key virulence determinants that directly impact pathogen adaptation and survival and the infection process. To establish a comprehensive baseline of PPIs in C. neoformans and explore these interactions to infer functional roles for uncharacterized proteins, we applied size exclusion chromatography coupled with mass spectrometry to the secreted and cellular proteomes of the fungi. As a result, 216 and 1699 unique proteins were identified across 24 secretome and proteome fractions, respectively. The predicted secretome networks included expected proteins associated with vesicles and virulence, indicating a role in extracellular defense. Whereas the cryptococcal proteome highlighted interactions among proteins with defined roles in fungal virulence for protein stability and thermotolerance, including two previously uncharacterized proteins, CNAG_00287 and CNAG_05199, putatively involved in complex formation with heat-shock proteins (HSP). Based on sequence and structure homology, we propose that CNAG_00287 is a tetratricopeptide repeat-containing co-chaperone that modulates Hsp 70 activity and CNAG_05199 functions as a Hsp70. We validated the thermotolerance role of CNAG_00287 in heat-related stress, as its absence significantly impaired fungal growth in nutrient-limited media at 37 {degrees}C. Together, this work resolves virulence-associated PPIs within C. neoformans and reveals new molecular regulators of thermotolerance that underpin fungal pathogenicity.

microbiology↗
bioRxiv2026

Environmental filtering and host identity collectively shape root-associated microbiomes of Ericaceae and ectomycorrhizal plants in fumarole fields

Background Symbiosis with microbes is a key strategy that has enabled plants to colonize extreme environments. Since the benefits conferred by root-associated microbes depend on both environmental conditions and host-microbe combinations, plant adaptation to harsh environments is closely linked to the assembly of root microbial communities. Understanding how environmental and host filtering jointly shape these communities is therefore fundamental to elucidating the mechanisms underlying plant adaptation to extreme environments. Results In this study, we investigated the differentiation of root-associated prokaryotic and fungal communities and individual operational taxonomic units (OTUs) across two contrasting habitats surrounding fumaroles, solfatara-field and forest-edge habitats, and six dominant Ericaceae and ectomycorrhizal plant taxa. Prokaryotic and fungal OTUs rarely exhibited strong preferences for both habitat and host identity. Instead, many of prokaryotic and fungal OTUs specialized to one of these niches, collectively generating root microbial communities differentiated by both factors. Nonetheless, striking specializations in habitat and host niches were observed in the fungal family Hyaloscyphaceae (Helotiales). To gain insight into the evolutionary basis of microbial specialization, we examined phylogenetic signals in preference phenotypes. The resulting weak phylogenetic signals in these preference phenotypes further suggest that this fungal clade has undergone substantial ecological divergence. Conclusion Overall, our findings indicate that root-associated microbial communities in extreme environments are assembled through the accumulation of microbial taxa specialized to either habitat or host, and that strong ecological specialization in fungi can arise with little phylogenetic constraint.

microbiology↗