The association between sterilizing activity and drug distribution into tuberculosis lesions.
Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside. In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration may contribute to treatment outcome has wide implications for TB.
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Brendan
B
Prideaux
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Laura E
LE
Via
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Matthew D
MD
Zimmerman
International Tuberculosis Research Center, Changwon, Republic of Korea.
Seokyong
S
Eum
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Jansy
J
Sarathy
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Paul
P
O'Brien
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Chao
C
Chen
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Firat
F
Kaya
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Danielle M
DM
Weiner
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Pei-Yu
PY
Chen
International Tuberculosis Research Center, Changwon, Republic of Korea.
Taeksun
T
Song
International Tuberculosis Research Center, Changwon, Republic of Korea.
Myungsun
M
Lee
Asan Medical Center, Seoul, Republic of Korea.
Tae Sun
TS
Shim
Pusan National University Hospital, Pusan, Republic of Korea.
Jeong Su
JS
Cho
National Medical Center, Seoul, Republic of Korea.
Wooshik
W
Kim
Department of Microbiology and Institute of Immunology and Immunological Disease, Yonsei University College of Medicine, Seoul, Republic of Korea.
Sang Nae
SN
Cho
Pulmonary Clinical Medicine, Cardiovascular Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Kenneth N
KN
Olivier
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.|Institute of Infectious Disease and Molecular Medicine, Department of Clinical Laboratory Sciences, University of Cape Town, Cape Town, South Africa.
Clifton E
CE
Barry
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
Véronique
V
Dartois
D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011718:Pyrazinamide / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism
D000995:Antitubercular Agents; D011718:Pyrazinamide; D012293:Rifampin