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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

Mapping the subcellular pharmacokinetic-pharmacodynamic landscape: a systems-pharmacology framework for predicting combination therapies against intracellular bacterial infections

  • Venkata Bharat Kumar Pinnelli1
  • Surendra Babu Thangachi2
  • C. A. Jayashankar3
  • Venkataramana Kandi4
  • G. R. Manish5
  • Koshy T. Sam3
  • Prafulla Kumar Raju Bhupathi Raju3
  • Atul Srinivas Sucharitha3
  • Ankita Barman3
  • G. Sainath3
  • Kabir Singal3
5 affiliations
  1. 1Department of Biochemistry, Vydehi Institute of Medical Sciences and Research Centre
  2. 2Department of Anatomy, Vydehi Institute of Medical Sciences and Research Centre
  3. 3Department of General Medicine, Vydehi Institute of Medical Sciences and Research Centre
  4. 4Department of Microbiology, Prathima Institute of Medical Sciences, Karimnagar
  5. 5Department of General Medicine, Akash Institute of Medical Sciences and Research Centre
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Abstract

Intracellular bacterial pathogens represent one of the most formidable challenges in contemporary medicine. By exploiting host cellular niches, these organisms evade immune surveillance and withstand conventional antibiotic therapies, establishing persistent reservoirs that are difficult to eradicate. Although antibiotic combinations, host-directed interventions, and drug repurposing have shown promise, conventional discovery pipelines rarely capture the dynamic and compartmentalized nature of the intracellular environment. This review proposes a systems pharmacology framework centered on subcellular pharmacokinetic/pharmacodynamic (Sub-PK/PD) profiling to predict and optimize intracellular combination therapies. Mechanistic and translational studies of intracellular drug disposition, host–pathogen metabolism, computational combination design, and biomimetic infection models were synthesized in a targeted narrative review. Particular attention was given to spatially resolved measurements, dual ribonucleic acid (RNA) sequencing, metabolic flux analysis, machine learning, and organ-on-a-chip platforms. Pathogen-containing vacuoles, phagolysosomes, the host cytosol, lipid-rich macrophages, and tissue lesions impose distinct barriers to drug ionization, accumulation, stability, and target engagement. Persistent infection also produces reciprocal metabolic rewiring: host pathways supply carbon, nitrogen, lipids, metals, and reducing equivalents, while bacterial stress programs alter growth and antibiotic susceptibility. Integrating these processes can reveal shared metabolic bottlenecks suitable for combinations of pathogen-directed and host-directed agents. Computational models can prioritize combinations, but their predictions require validation under physiologically realistic concentration–time profiles. Linking systems biology to localized Sub-PK/PD provides a practical roadmap for designing niche-specific regimens. Such regimens could improve clearance of persistent intracellular reservoirs, reduce ineffective exposure, and limit the emergence of antimicrobial resistance.

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Cite

BibTeXRIS
BibTeX
@article{pinnelli2026mapping,
  title = {{Mapping the subcellular pharmacokinetic-pharmacodynamic landscape: a systems-pharmacology framework for predicting combination therapies against intracellular bacterial infections}},
  author = {Venkata Bharat Kumar Pinnelli and Surendra Babu Thangachi and C. A. Jayashankar and Venkataramana Kandi and G. R. Manish and Koshy T. Sam and Prafulla Kumar Raju Bhupathi Raju and Atul Srinivas Sucharitha and Ankita Barman and G. Sainath and Kabir Singal},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1994202},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1994202/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Mapping the subcellular pharmacokinetic-pharmacodynamic landscape: a systems-pharmacology framework for predicting combination therapies against intracellular bacterial infections
AU  - Venkata Bharat Kumar Pinnelli
AU  - Surendra Babu Thangachi
AU  - C. A. Jayashankar
AU  - Venkataramana Kandi
AU  - G. R. Manish
AU  - Koshy T. Sam
AU  - Prafulla Kumar Raju Bhupathi Raju
AU  - Atul Srinivas Sucharitha
AU  - Ankita Barman
AU  - G. Sainath
AU  - Kabir Singal
PY  - 2026
DA  - 2026/10/22
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1994202
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1994202/full
AB  - Intracellular bacterial pathogens represent one of the most formidable challenges in contemporary medicine. By exploiting host cellular niches, these organisms evade immune surveillance and withstand conventional antibiotic therapies, establishing persistent reservoirs that are difficult to eradicate. Although antibiotic combinations, host-directed interventions, and drug repurposing have shown promise, conventional discovery pipelines rarely capture the dynamic and compartmentalized nature of the intracellular environment. This review proposes a systems pharmacology framework centered on subcellular pharmacokinetic/pharmacodynamic (Sub-PK/PD) profiling to predict and optimize intracellular combination therapies. Mechanistic and translational studies of intracellular drug disposition, host–pathogen metabolism, computational combination design, and biomimetic infection models were synthesized in a targeted narrative review. Particular attention was given to spatially resolved measurements, dual ribonucleic acid (RNA) sequencing, metabolic flux analysis, machine learning, and organ-on-a-chip platforms. Pathogen-containing vacuoles, phagolysosomes, the host cytosol, lipid-rich macrophages, and tissue lesions impose distinct barriers to drug ionization, accumulation, stability, and target engagement. Persistent infection also produces reciprocal metabolic rewiring: host pathways supply carbon, nitrogen, lipids, metals, and reducing equivalents, while bacterial stress programs alter growth and antibiotic susceptibility. Integrating these processes can reveal shared metabolic bottlenecks suitable for combinations of pathogen-directed and host-directed agents. Computational models can prioritize combinations, but their predictions require validation under physiologically realistic concentration–time profiles. Linking systems biology to localized Sub-PK/PD provides a practical roadmap for designing niche-specific regimens. Such regimens could improve clearance of persistent intracellular reservoirs, reduce ineffective exposure, and limit the emergence of antimicrobial resistance.
SN  - 1663-9812
ER  -