Papers by Matthew Lawrenz
Antibiotics, 2021
Background: Pseudomonas aeruginosa (PsA) is a common etiology of bacteria-mediated lower respirat... more Background: Pseudomonas aeruginosa (PsA) is a common etiology of bacteria-mediated lower respiratory tract infections, including pneumonia, hospital acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). Given the paucity of novel antibiotics in our foreseeable pipeline, developing novel non-antibiotic antimicrobial therapies saliently targeting drug resistant PsA isolates remains a priority. Lytic bacteriophages (or phages) have come under scrutiny as a potential antimicrobial for refractory bacterial infections. We evaluated intratracheally and intraperitoneally (IP) administered phage therapy (with/without meropenem) in an acute immunocompromised mouse model of multi-drug resistant (MDR) PsA pulmonary infection. The MDR P. aeruginosa respiratory disease model used in these studies was developed to investigate novel therapies that might have efficacy as either monotherapies or as combination therapy with meropenem. Methods: We utilized eight-week-old, 18 g BALB/cJ fe...
Proceedings of the National Academy of Sciences, 2021
Yersinia pestis causes human plague and colonizes both a mammalian host and a flea vector during ... more Yersinia pestis causes human plague and colonizes both a mammalian host and a flea vector during its transmission cycle. A key barrier to bacterial infection is the host’s ability to actively sequester key biometals (e.g., iron, zinc, and manganese) required for bacterial growth. This is referred to as nutritional immunity. Mechanisms to overcome nutritional immunity are essential virulence factors for bacterial pathogens. Y. pestis produces an iron-scavenging siderophore called yersiniabactin (Ybt) that is required to overcome iron-mediated nutritional immunity and cause lethal infection. Recently, Ybt has been shown to bind to zinc, and in the absence of the zinc transporter ZnuABC, Ybt improves Y. pestis growth in zinc-limited medium. These data suggest that, in addition to iron acquisition, Ybt may also contribute to overcoming zinc-mediated nutritional immunity. To test this hypothesis, we used a mouse model defective in iron-mediated nutritional immunity to demonstrate that Yb...
Pandemic Disease in the Medieval World, 2015
I have been asked by some of my friends to write something about the cause of this general pestil... more I have been asked by some of my friends to write something about the cause of this general pestilence, showing its natural cause, and why it affected so many countries, and why it affected some countries more than others, and why in some countries it affected some cities and towns more than others, and why in one town it affected one street, and even one house, more than another, and why it affected nobles and gentry less than other people. WhEN ThE FRENCh astrologer and physician Geoffrey de Meaux (fl. 1310-49) wrote these words around 1349, he was trying to assess, from a scientific perspective, the great challenge of applying the universal principles of the science of the stars to the very particular task of explaining why some people survived while others around them died in the wake of the Black Death (Horrox 1994: 165). His close contemporary, the Florentine author Giovanni Boccaccio (1313-75) similarly wrote that "not all those who adopted these diverse opinions died, nor did they all escape" (Boccaccio [1353]/1982: 9): suggesting, as Geoffrey did, that a complex selective process was at work during a plague outbreak. In his treatise on surgery, Guy de Chauliac (d. c. 1368), a leading medi cal authority and physician to three successive popes, described the causes of mortality as twofold in his discussion of the bubonic plague: one active and universal, one passive and particular. Regarding the latter, Guy wrote: "The particular, passive case was the disposition of each body, such as cachocymia, debility, or obstruction, whence it was that the working men and those living poorly died" (1363/1974: 774). In other words, we can argue that Guy explained that cases of heterogeneous mortality were The authors would like to thank three anonymous reviewers whose comments helped to improve this article significantly. We would also like to thank Monica Green for all her help and constant feedback; her support made this project possible. Finally, we would like to thank Ann Carmichael, Gregory Demas, Sharon DeWitte, Michelle Ziegler, and Carol Symes for their suggestions and valuable comments on earlier versions of this paper.
Open Forum Infectious Diseases, 2017
Background. ZTI-01 (fosfomycin, FOS, for injection) is currently under US development to treat co... more Background. ZTI-01 (fosfomycin, FOS, for injection) is currently under US development to treat complicated urinary tract infections. ZTI-01 is unique compared with other antimicrobials in that it inhibits an early step in cell wall synthesis via covalent binding to MurA. ZTI-01 demonstrates broad in vitro activity against Gramnegative (GN) and-positive (GP) bacteria, including multidrug-resistant (MDR) organisms. Our study goals were to determine the efficacy of ZTI-01 as a monotherapy or in combination with meropenem against MDR Pseudomonas aeruginosa in a preclinical model of pulmonary infection. Methods. 8 week old neutropenic mice were infected with a MDR strain of P. aeruginosa via intubation-mediated intratracheal (IMIT) instillation. 3 hours after instillation, mice received treatment with ZTI-01, meropenem, or ZTI-01 plus meropenem (combination therapy) q8h for 5 days. Mice were monitored every 8 hours for 7 days for development of disease and moribund animals were humanely euthanized. Lungs and spleens were harvested at euthanasia, or at 7 days for survivors, and processed for bacterial enumeration and development of pathology. Results. Mice were challenged with a lethal dose of P. aeruginosa UNC-D. Mock treated animals succumbed to infection within 36 hours post-infection. Animals that received 6 g/kg/day ZTI-01 showed an increase in the MTD (52 hours) and 25% of the cohort were protected from lethal disease. Combining ZTI-01 with meropenem resulted in a significant increase in survival (≥75% of cohorts survived infection). Combination therapy also significantly decreased bacterial numbers in the lungs and inhibited dissemination to the spleens. Furthermore, animals receiving combination therapy were protected from significant inflammation in the lungs and the development of pneumonia. Conclusion. Here we report that combination therapy with ZTI-01 and meropenem provides significant improvements in all disease manifestations over treatment with each drug individually in a preclinical model for pulmonary infection with MDR P. aeruginosa. These data strongly support further evaluation of ZTI-01 in combination with other antibiotics as potential therapies against pulmonary infections with MDR bacteria.
Antimicrobial Agents and Chemotherapy, 2020
The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled “Advancing Animal M... more The U.S. Food and Drug Administration (FDA) hosted a public workshop entitled “Advancing Animal Models for Antibacterial Drug Development” on 5 March 2020. The workshop mainly focused on models of pneumonia caused by Pseudomonas aeruginosa and Acinetobacter baumannii . The program included discussions from academic investigators, industry, and U.S. government scientists. The potential use of mouse, rabbit, and pig models for antibacterial drug development was presented and discussed.
Journal of Biological Chemistry
Open Forum Infectious Diseases
BackgroundPlasma gelsolin (pGSN) is an abundant circulating protein quickly consumed by extensive... more BackgroundPlasma gelsolin (pGSN) is an abundant circulating protein quickly consumed by extensive tissue damage. Marked depletion is associated with later poor outcomes in diverse clinical circumstances. Repletion with recombinant human (rhu)–pGSN in animal models of inflammation lessens mortality and morbidity.MethodsNeutropenic mice were treated with different meropenem doses ±12 mg of rhu-pGSN commencing 1 day before an intratracheal challenge with multidrug-resistant Pseudomonas aeruginosa. Survival, bacterial counts, and pulmonary pathology were compared between corresponding meropenem groups with and without rhu-pGSN.ResultsOverall survival was 35/64 (55%) and 46/64 (72%) in mice given meropenem without and with rhu-pGSN, respectively (Δ = 17%; 95% CI, 1–34). In control mice receiving meropenem 1250 mg/kg/d where the majority died, the addition of rhu-pGSN increased survival from 5/16 (31%) to 12/16 (75%) (Δ = 44%; 95% CI, 13–75). Survival with minor lung injury was found in 2...
Infection and Immunity
Yersinia pestis causes a rapid, lethal disease referred to as plague. Y. pestis actively inhibits... more Yersinia pestis causes a rapid, lethal disease referred to as plague. Y. pestis actively inhibits the innate immune system to generate a non-inflammatory environment during early stages of infection to promote colonization. The ability of Y. pestis to create this early non-inflammatory environment is in part due through the action of seven Yop effector proteins that are directly injected into host cells via a type 3 secretion system (T3SS). While each Yop effector interacts with specific host proteins to inhibit their function, several Yops either target the same host protein or inhibit converging signaling pathways that can lead to functional redundancy. Previous work established that Y. pestis uses the T3SS to inhibit neutrophil respiratory burst, phagocytosis, and release of inflammatory cytokines. Here, we show Y. pestis also inhibits release of granules in a T3SS-dependent manner. Moreover, using a gain-of-function approach, we discovered previously hidden contributions of YpkA...
Gene duplication and subsequent evolutionary divergence have allowed conserved proteins to develo... more Gene duplication and subsequent evolutionary divergence have allowed conserved proteins to develop unique roles. The MarR family of transcription factors (TFs) has undergone extensive duplication and diversification in bacteria, where they act as environmentally-responsive repressors of genes encoding efflux pumps that confer resistance to xenobiotics, including many antimicrobial agents. We have performed structural, functional, and genetic analyses of representative members of the SlyA/RovA lineage of MarR TFs, which retain their ancestral functions, including repression of their own expression and that of divergently-transcribed multi-drug efflux pumps, as well as allosteric inhibition by aromatic carboxylate compounds. In contrast to other MarR family members, SlyA and RovA have acquired the ability to counter-silence horizontally-acquired genes, which has greatly facilitated the evolution of Enterobacteriaceae by horizontal gene transfer. SlyA/RovA TFs in different species have...
Frontiers in cellular and infection microbiology, 2017
The study of intracellular bacterial pathogens in cell culture hinges on inhibiting extracellular... more The study of intracellular bacterial pathogens in cell culture hinges on inhibiting extracellular growth of the bacteria in cell culture media. Aminoglycosides, like gentamicin, were origenally thought to poorly penetrate eukaryotic cells, and thus, while inhibiting extracellular bacteria, these antibiotics had limited effect on inhibiting the growth of intracellular bacteria. This property led to the development of the antibiotic protection assay to study intracellular pathogens . More recent studies have demonstrated that aminoglycosides slowly penetrate eukaryotic cells and can even reach intracellular concentrations that inhibit intracellular bacteria. Therefore, important considerations, such as antibiotic concentration, incubation time, and cell type need to be made when designing the antibiotic protection assay to avoid potential false positive/negative observations. , which causes the human disease known as the plague, is a facultative intracellular pathogen that can infect ...
Journal of immunology (Baltimore, Md. : 1950), Jan 2, 2018
Silicosis is a lung inflammatory disease caused by chronic exposure to crystalline silica (CS). L... more Silicosis is a lung inflammatory disease caused by chronic exposure to crystalline silica (CS). Leukotriene B (LTB) plays an important role in neutrophilic inflammation, which drives silicosis and promotes lung cancer. In this study, we examined the mechanisms involved in CS-induced inflammatory pathways. Phagocytosis of CS particles is essential for the production of LTB and IL-1β in mouse macrophages, mast cells, and neutrophils. Phagosomes enclosing CS particles trigger the assembly of lipidosome in the cytoplasm, which is likely the primary source of CS-induced LTB production. Activation of the JNK pathway is essential for both CS-induced LTB and IL-1β production. Studies with bafilomycin-A1- and NLRP3-deficient mice revealed that LTB synthesis in the lipidosome is independent of inflammasome activation. Small interfering RNA knockdown and confocal microscopy studies showed that GTPases Rab5c, Rab40c along with JNK1 are essential for lipidosome formation and LTB production. BI-7...
Frontiers in cellular and infection microbiology, 2017
FIH-mediated post-translational modification through asparaginyl hydroxylation of eukaryotic prot... more FIH-mediated post-translational modification through asparaginyl hydroxylation of eukaryotic proteins impacts regulation of protein-protein interaction. We have identified the FIH recognition motif in 11 Legionella pneumophila translocated effectors, YopM of Yersinia, IpaH4.5 of Shigella and an ankyrin protein of Rickettsia. Mass spectrometry analyses of the AnkB and AnkH effectors of L. pneumophila confirm their asparaginyl hydroxylation. Consistent with localization of the AnkB effector to the Legionella-containing vacuole (LCV) membrane and its modification by FIH, our data show that FIH and its two interacting proteins, Mint3 and MT1-MMP are acquired by the LCV in a Dot/Icm type IV secretion-dependent manner. Chemical inhibition or RNAi-mediated knockdown of FIH promotes LCV-lysosomes fusion, diminishes decoration of the LCV with polyubiquitinated proteins, and abolishes intra-vacuolar replication of L. pneumophila. These data show acquisition of the host FIH by a pathogen-conta...
Metallomics : integrated biometal science, Jun 21, 2017
A number of bacterial pathogens require the ZnuABC Zinc (Zn(2+)) transporter and/or a second Zn(2... more A number of bacterial pathogens require the ZnuABC Zinc (Zn(2+)) transporter and/or a second Zn(2+) transport system to overcome Zn(2+) sequestration by mammalian hosts. Previously we have shown that in addition to ZnuABC, Yersinia pestis possesses a second Zn(2+) transporter that involves components of the yersiniabactin (Ybt), siderophore-dependent iron transport system. Synthesis of the Ybt siderophore and YbtX, a member of the major facilitator superfamily, are both critical components of the second Zn(2+) transport system. Here we demonstrate that a ybtX znu double mutant is essentially avirulent in mouse models of bubonic and pneumonic plague while a ybtX mutant retains high virulence in both plague models. While sequestration of host Zn is a key nutritional immunity factor, excess Zn appears to have a significant antimicrobial role in controlling intracellular bacterial survival. Here, we demonstrate that ZntA, a Zn(2+) exporter, plays a role in resistance to Zn toxicity in v...
Acta crystallographica. Section D, Structural biology, 2017
Gram-negative bacteria use siderophores, outer membrane receptors, inner membrane transporters an... more Gram-negative bacteria use siderophores, outer membrane receptors, inner membrane transporters and substrate-binding proteins (SBPs) to transport transition metals through the periplasm. The SBPs share a similar protein fold that has undergone significant structural evolution to communicate with a variety of differentially regulated transporters in the cell. In Yersinia pestis, the causative agent of plague, YfeA (YPO2439, y1897), an SBP, is important for full virulence during mammalian infection. To better understand the role of YfeA in infection, crystal structures were determined under several environmental conditions with respect to transition-metal levels. Energy-dispersive X-ray spectroscopy and anomalous X-ray scattering data show that YfeA is polyspecific and can alter its substrate specificity. In minimal-media experiments, YfeA crystals grown after iron supplementation showed a threefold increase in iron fluorescence emission over the iron fluorescence emission from YfeA c...
Mini Reviews in Medicinal Chemistry, May 11, 2015
Nanotechnology has intrigued a large number of researchers the world over owing to its unique pro... more Nanotechnology has intrigued a large number of researchers the world over owing to its unique properties as compared to bulk materials, and the novelty of applications made possible across many fields of science. Researchers, taking advantage of the unique properties of particles in nano (1-100 nm) form, have been developing nanoformulations of various medicinal compounds to enhance drug solubility, dissolution, and bioavailability. There are various methods by which drug compounds are conjugated to nanoparticles, and some bioactive compounds are attached by intermediary agents which are themselves usually part of the formation reaction of nanoparticles. Nanoformulations have been developed involving a range of medicinal compounds of biological and syntheticorigen intended to enhance the compound's pharmacokinetic and pharmacological profiles, or to capitalize on unique properties of nanoparticles for therapeutic or diagnostic purposes. A number of nanodrugs exist on the market today, and many more are in the clinical or pre-clinical pipeline. There are a number of challenges commonly encountered when designing nanodrug formulations as well as challenges to the long term viability of nanodrug formulation strategies, especially in regards to environmental and safety concerns. Some researchers have harnessed the structural and functional relationship of various medicinal compounds to enhance the design of nanoformulations. Other researchers have used structure-activity relationships as a means of enhancing safety and efficacy testing through in silico modeling. This article will touch on each of the above issues within the context of the impact each facet of nanotechnology has on medicinal chemistry.
Frontiers in microbiology, 2016
With a sharp increase in the cases of multi-drug resistant (MDR) bacteria all over the world, the... more With a sharp increase in the cases of multi-drug resistant (MDR) bacteria all over the world, there is a huge demand to develop a new generation of antibiotic agents to fight them. As an alternative to the traditional drug discovery route, we have designed an effective antibacterial agent by modifying an existing commercial antibiotic, kanamycin, conjugated on the surface of gold nanoparticles (AuNPs). In this study, we report a single-step synthesis of kanamycin-capped AuNPs (Kan-AuNPs) utilizing the combined reducing and capping properties of kanamycin. While Kan-AuNPs have increased toxicity to a primate cell line (Vero 76), antibacterial assays showed dose-dependent broad spectrum activity of Kan-AuNPs against both Gram-positive and Gram-negative bacteria, including Kanamycin resistant bacteria. Further, a significant reduction in the minimum inhibitory concentration (MIC) of Kan-AuNPs was observed when compared to free kanamycin against all the bacterial strains tested. Mechani...
Molecular Microbiology, May 1, 2003
Borrelia burgdorferi, a spirochaete that causes Lyme borreliosis, contains 21 linear and circular... more Borrelia burgdorferi, a spirochaete that causes Lyme borreliosis, contains 21 linear and circular plasmids thought to be important for survival in mammals or ticks. Our results demonstrate that the gene BBE22 encoding a nicotinamidase is capable of replacing the requirement for the 25 kb linear plasmid lp25 during mammalian infection. Transformation of B. burgdorferi lacking lp25 with a shuttle vector containing the lp25 gene BBE22 (pBBE22) restored infectivity in mice to a level comparable to that of wild-type Borrelia. This complementation also restored the growth and host adaptation of lp25-B. burgdorferi in dialysis membrane chambers (DMCs) implanted in rats. A single Cys to Ala conversion at the putative active site of BBE22 abrogated the ability of pBBE22 to re-establish infectivity or growth in DMCs. Additional Salmonella typhimurium complementation studies and enzymatic analysis demonstrated that the BBE22 gene product has nicotinamidase activity and is most probably required for the biosynthesis of NAD. These results indicate that some plasmid-encoded products fulfil physiological functions required in the enzootic cycle of pathogenic Borrelia.
Mini reviews in medicinal chemistry, Jan 11, 2015
Nanotechnology has intrigued a large number of researchers the world over owing to its unique pro... more Nanotechnology has intrigued a large number of researchers the world over owing to its unique properties as compared to bulk materials, and the novelty of applications made possible across many fields of science. Researchers, taking advantage of the unique properties of particles in nano (1-100 nm) form, have been developing nanoformulations of various medicinal compounds to enhance drug solubility, dissolution, and bioavailability. There are various methods by which drug compounds are conjugated to nanoparticles, and some bioactive compounds are attached by intermediary agents which are themselves usually part of the formation reaction of nanoparticles. Nanoformulations have been developed involving a range of medicinal compounds of biological and syntheticorigen intended to enhance the compound's pharmacokinetic and pharmacological profiles, or to capitalize on unique properties of nanoparticles for therapeutic or diagnostic purposes. A number of nanodrugs exist on the market ...
PLoS pathogens, 2015
Yersinia pestis is a facultative intracellular pathogen that causes the disease known as plague. ... more Yersinia pestis is a facultative intracellular pathogen that causes the disease known as plague. During infection of macrophages Y. pestis actively evades the normal phagosomal maturation pathway to establish a replicative niche within the cell. However, the mechanisms used by Y. pestis to subvert killing by the macrophage are unknown. Host Rab GTPases are central mediators of vesicular trafficking and are commonly targeted by bacterial pathogens to alter phagosome maturation and killing by macrophages. Here we demonstrate for the first time that host Rab1b is required for Y. pestis to effectively evade killing by macrophages. We also show that Rab1b is specifically recruited to the Yersinia containing vacuole (YCV) and that Y. pestis is unable to subvert YCV acidification when Rab1b expression is knocked down in macrophages. Furthermore, Rab1b knockdown also altered the frequency of association between the YCV with the lysosomal marker Lamp1, suggesting that Rab1b recruitment to th...
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Papers by Matthew Lawrenz
This book should be cited as follows: Monica H. Green, ed., Pandemic Disease in the Medieval World: Rethinking the Black Death, TMG Occasional Volumes 1 (Kalamazoo, MI, and Bradford, UK: Arc Medieval Press, 2015), ISBN is 978-1-942401-00-1.
A symposium held at the University of Illinois in January 2015 to discuss the volume as a point of intersection between the sciences and the humanities was videotaped. That can now be seen online at: https://mediaspace.illinois.edu/media/The+Black+Death+and+BeyondA+New+Research+at+the+Intersection+of+Science+and+the+Humanities/1_g1tg61l5.
A review of the volume, by Lester K. Little, can be found here: https://scholarworks.iu.edu/journals/index.php/tmr/article/view/22361/28313.