Research
BASIC RESEARCH
Our research focuses on the biology of the peptidoglycan of Mycobacterium tuberculosis, the organism that causes tuberculosis, and Mycobacterium abscessus, a related bacterium that causes opportunistic infections. We study basic mechanisms associated with peptidoglycan physiology but with an intent to leverage our findings to develop tools that will be useful in the clinic to treat mycobacterial infections.
Peptidoglycan is the exoskeleton of bacteria that not only provides structural rigidity and cell shape but also several vital physiological functions. Breaching this structure is often lethal to bacteria. We are exploring fundamental mechanisms by which bacteria synthesize and preserve their peptidoglycan. Although our lab uses genetic, biochemical and biophysical approaches to study the peptidoglycan, we pursue questions irrespective of the expertise required to answer those questions. It is through these studies that we identified synergy between two beta-lactam antibiotics against select mycobacteria.
Example publications:
Gupta R, Lavollay M, Mainardi J, Arthur M, Bishai WR, Lamichhane G. The Mycobacterium tuberculosis gene, ldtMt2, encodes a non-classical transpeptidase required for virulence and resistance to amoxicillin. Nature Medicine. 2010; 16, 466-9. PMID:20305661
Schoonmaker MK, Bishai WR, Lamichhane G. Non-classical cross-linking of the peptidoglycan of Mycobacterium tuberculosis is required for cell morphology, virulence and resistance to β-lactams and glycopeptides. Journal of Bacteriology. 2014; 196 (7), 1394-402. PMID 24464457
Galanis C, Maggioncalda EC, Kumar P, Lamichhane G. Glby, encoded by MAB_3167c, is required for in vivo growth of M. abscessus and exhibits mild β-lactamase activity. 2022. Journal of Bacteriology. Apr 5:e0004622. PMID. 35380462 doi: 10.1128/jb.00046-22
That Wall
In their realm of science's grace,
Where wonders of deadly bacteria they chase,
With fervent hearts and minds that yearn,
They delve into cell walls to discern.
Peptidoglycan, a fortress strong,
In every bacterium, the exoskeleton it is lifelong,
Fundamental secrets it conceals,
In their lab, curiosity reveals.
With molecular probes,
Drs. Basta, Kumar and Galanis peer inside,
Unraveling mysteries they can't hide,
Unknown mechanisms, they seek to trace,
In the molecular world's embrace.
As petals bloom 'neath morning dew,
In their lab, knowledge grew,
From cell to cell, they chart their way,
A path to truths that sway and sway.
Amidst the tapestry of life's design,
They seek the answers they'll align,
Yet beyond knowledge, they aspire,
A grander purpose, a greater desire,
For in these findings, they see a light,
To combat pathogens, a righteous fight.
New antibiotics, their hearts do yearn,
To safeguard lives, their fervent concern,
With insights gained from peptidoglycan's reign,
A shield against infections they'll sustain.
In Lamichhane's lab, hope does reside,
Where science and compassion coincide,
With every discovery, a step they take,
For a world where healing is awake.
Mycobacterium abscessus - the organism and a mouse model
Mycobacterium abscessus is one of the non-tuberculous mycobacteria that can cause soft tissue disease. Those with compromised lung function, specifically cystic fibrosis, bronchiectasis and COPD patients are at a higher risk of contracting M. abscessus infection. We study the basic physiology of this organism and genetic determinants of its virulence. We have also developed a mouse model of M. abscessus lung infection which can be used to evaluate efficacies of experimental therapeutics and virulence of M. abscessus isolates.
Example publications:
Maggioncalda EC, Story-Roller E, Mylius J, Illei P, Basaraba RJ, Lamichhane G. A mouse model of pulmonary Mycobacteroides abscessus infection. 2020. Scientific Reports. 10. https://rdcu.be/b2i1h PMID 32111900
Story-Roller E, Maggioncalda EC, Lamichhane G. Synergistic efficacy of β-lactam combinations against Mycobacterium abscessus pulmonary infection in mice. 2019. Antimicrobial Agents and Chemotherapy. 63(8) PMID 31109979
Rimal B, Batchelder HR, Story-Roller E, Panthi CM, Tabor C, Nuermberger EL, Townsend CA, Lamichhane G. T405, a new penem, exhibits in vivo efficacy against M. abscessus and synergy with β-lactams imipenem and cefditoren. 2022. Antimicrobial Agents and Chemotherapy. 66(6):e0053622. PMID 35638855
Sriram D, Wahi R, Maggioncalda EC, Panthi CM, Lamichhane G. Clofazimine as a comparator for preclinical efficacy evaluations of experimental therapeutics against M. abscessus infection in mice. 2022. Tuberculosis.137:102268 DOI: 10.1016/j.tube.2022.102268 PMID: 36228452
In the NTM labs at Hopkins, a quest takes flight,
To battle Mycobacterium's stealthy might,
Their minds ablaze with unwavering aim,
Developing tools to know its make.
Amidst the trials of the pandemic's day,
Dr. Emily Maggioncalda, led the way,
Determined soul, relentless stride,
Forging a mouse model to match the tide.
Mycobacterium abscessus, an emerging foe,
A puzzle unsolved, a menace to know,
In this mouse model, its secrets unfurled,
A beacon of hope to find good cures.
Dr. Elizabeth Story-Roller, a soul determined,
In pre-clinical trials, she's been found,
Demonstrating how drugs may quell,
The disease that haunts, the stories it tells.
With hearts alight and passion embraced,
The Hopkins team, a force interlaced,
Doctors Ingatius, Lippincott and Belz and their clinical team,
With next-door mycodetectives Parish and Armstrong,
and scientists in the basic science labs, hand in hand,
Bringing new treatments to a troubled land.
In the NTM clinic's nurturing care,
They combine their strengths, a synergy rare,
Their aim united, their purpose clear,
To ease the suffering of NTM patients, to banish fear.
Through research and new knowledge, they forge ahead,
With empathy for patients, where hope is bred,
In our lab, a beacon burns,
For NTM patients, their resolve returns.
Across the world, their work extends,
A lifeline to those whom illness rends,
In unity they strive, their mission to mend,
A story of hope, where new chapters ascend.
-The Lamichhane Lab
TRANSLATIONAL RESEARCH
We seek every opportunity to translate findings from our basic research. For example, our basic studies of non-classical transpeptidases that also synthesize the peptidoglycan, L,D-transpeptidases, revealed that they are selectively inhibited by a sub-class of beta-lactam antibiotics. Based on this finding, beginning 2010, we proposed use of dual beta-lactams (combination of beta-lactams, one that effectively inhibits PBPs and other that inhibits L,D-transpeptidases) for treatment of mycobacterial infections. We have demonstrated the utility of this approach in both in vitro and animal models. Our translational research includes the two programs described below (TREAT and DR BaGeL) and has led to the following US Patents.
US Patent 9,273,341: Methods for Treatment of Bacterial Infections. Lamichhane G, Gupta R, Bishai WR, Lavollay M, Mainardi J, Arthur M. Methods for Treatment of Bacterial Infections. Awarded on 1 March 2016.
US Patent 10,434,089: Avibactam and Carbapenems Antibacterial Agents. Lamichhane G. Awarded on 08 October 2019.
US Patent 10,695,322: Inhibitors of Bacterial Growth. Lamichhane G, Freundlich JS, Ekins S, Kumar P, Kaushik A, Li SG, Townsend CA, Lloyd E, Parrish N. Awarded on June 30, 2020.
TREAT (Taskforce for Resistance Emergence & Antibacterial Technology)
TREAT was established in 2012. There is an immense need for new antimicrobials that are effective against bacterial strains that are either susceptible or resistant to currently available drugs. Our aim is to make necessary effort to systematically develop new antimicrobials. This will include chemical synthesis of new compounds, their evaluation in vitro, in animal models and in human clinical trials. Within this program, we also study the molecular mechanisms that confer drug resistance in bacteria. Our laboratory collaborates with several like-minded investigators ranging from synthetic chemists, biochemists and clinical translators. We work closely with a larger university-wide program, Johns Hopkins Integrated Center for Combating Antimicrobial Resistant Bacteria, HI-CARB. So far, several papers and two patents have resulted from this effort.
Example publications:
Story-Roller E, Maggioncalda EC, Lamichhane G. Synergistic efficacy of β-lactam combinations against Mycobacterium abscessus pulmonary infection in mice. 2019. Antimicrobial Agents and Chemotherapy. 63(8) PMID 31109979
Kumar P, Kaushik A, Lloyd EP, Li SG, Mattoo R, Ammerman NC, Lloyd DT, Perryman AL, Ekins S, Ginell SL, Townsend CA, Freundlich JS, Lamichhane G. New antibacterials targeting non-classical transpeptidases. Nature Chemical Biology. 2017. 13; 54-61. PMID 27820797
Kumar P, Chauhan V, Silva JRA, Lameira J, d’Andrea F, Li S, Ginell SL, Freundlich JS, Alves CN, Bailey S, Cohen KA, Lamichhane G. Mycobacterium abscessus L,D-transpeptidases are susceptible to inactivation by carbapenems and cephalosporins but not penicillins. Antimicrobial Agents and Chemotherapy. 2017. 61 (10) e00866-17 PMID 28760902
Mattoo R, Lloyd EP, Kaushik A, Kumar P, Brunelle JL, Townsend CA, Lamichhane G. LdtMav2, a nonclassical transpeptidase and susceptibility of Mycobacterium avium to carbapenems. 2017. Future Microbiology. 12(7): 595-607. PMID 28555497
Kaushik A, Pandey P, Makkar N, Parrish N, Singh U, Lamichhane G. Carbapenems and Rifampicin Exhibit Synergy Against Mycobacterium tuberculosis and Mycobacterium abscessus. Antimicrobial Agents and Chemotherapy. 2015. 59(10), 3561-67. PMID 26259792
DR BaGeL (Drug Resistant Bacterial Genome Library)
DR BaGeL is a program with a primary focus to generate, curate and disseminate whole genome sequences of clinically significant drug-resistant bacteria. The main objective of this program is to understand molecular mechanisms that can render bacteria resistant to new antibacterial candidates under development and to understand fundamental biology behind such molecular maneuvers by bacteria. We generate whole genome sequences of bacterial strains that are resistant to new or experimental antibacterials. We leverage these sequences to understand the genetic factors relevant to drug resistance emergence. Recently, this effort resulted in the discovery of a new protein in M. tuberculosis with beta-lactamase activity. This protein is encoded by a short ORF that was previous considered intergenic region (between Rv2421 and Rv2422).
Example publications:
Kumar P, Kaushik A, Bell D, Xia F, Stevens RL, Lamichhane G. Mutation in an unannotated protein confers carbapenem resistance in Mycobacterium tuberculosis. 2017. Antimicrobial Agents and Chemotherapy. 61(3)e02234-16. PMID 98069655