Dual Inhibition of Mycobacterial Fatty Acid Biosynthesis and Degradation by 2-Alkynoic Acids

Summary2-Hexadecynoic acid and 2-octadecynoic acid have cidal activity against Mycobacterium smegmatis and Mycobacterium bovis BCG. At subinhibitory concentrations, M. smegmatis rapidly transformed [1-14C]-2-hexadecynoic acid into endogenous fatty acids and elongated them into mycolic acids. Toxic concentrations of 2-hexadecynoic acid resulted in accumulation of 3-ketohexadecanoic acid, which blocked fatty acid biosynthesis, and 3-hexadecynoic acid, an inhibitor of fatty acid degradation. The combination of these two metabolites is necessary to achieve the inhibition of M. smegmatis. We conclude that 2- and 3-hexa/octadecynoic acids inhibit mycolic acid biosynthesis, fatty acid biosynthesis, and fatty acid degradation, pathways of significant importance for mycobacteria

Pengaruh Pemberian Biskuit Tepung Ikan Mujair dan Tepung Beras Merah terhadap Status Gizi Siswa SD di KecamatanLamasi

Penelitian ini bertujuan untuk mengetahui : 1) status gizi siswa SD Lamasi sebelum mengkonsumsi biskuit tepung ikan mujair dan tepung beras merah 2) status gizi siswa SD Lamasi setelah mengkonsumsi biskuit tepung ikan mujair dan tepung beras merah 3) pengaruh biskuit tepung ikan mujair dan tepung beras merah terhadap status gizi siswa SD Lamasi. Jenis penelitian yang digunakan adalah penelitian kuantitatif dengan metode eksperimen yaitu Quasi Experimental design dan Desain penelitian Randomized Controlled Trial (RCT) Single Blind Pre-post Study, jumlah sampel sebanyak 26 orang yang dipilih secara purposive sampling, dari 3 sekolah sebanyak 104 siswa SD kelas V di Kecamatan Lamasi, yang berumur 10-11 tahun. Data penelitian diperoleh dengan teknik angket (ffqdan food recall), wawancara (profilkeluarga), observasi (keadaanlingkungan), dan dokumentasi (data dinaspendidikandan data sekolah). Teknik analisis data yang digunakan adalah analisis deskriptif, uji T dan analisis regresi. Hasil penelitian menunjukkan 1) berkurangnya status gizi kurang siswa dari 11 sampel menjadi 10 sampel, dan meningkatnya status gizi ideal siswa dari 2 sampel menjadi 3 sampel setelah mengkonsumsi biskuit untuk kelompok kontrol, sedangkan untuk kelompok perlakuan sebelum dan setelah mengkonsumsi biskuit terdapat status gizi kurang sebanyak 12 sampel menjadi 11 sampel, dan status gizi ideal sebanyak 1 sampel menjadi 2 sampel. 2) Hasil pengujian pada tabel diketahui nilai t sebesar -1.573 dengan nilai P Value> 0,05 maka dapat disimpulkan bahwa tidak ada pengaruh yang signifikan atau lemah pada konsumsi biskuit tehadap status gizi siswa, dan nilai R = 0.312menunjukkan hubungan antara variabel bebas dan variabel terikat termasuk pada kategori lemah, variabel terikat atau R Square = 9,8% dan 90.2% dipengaruhi oleh faktor lain. Kata kunci: biskuit tepung ikan mujair dan tepung beras merah, status gizi

Multidrug-Resistant Tuberculosis in Panama Is Driven by Clonal Expansion of a Multidrug-Resistant Mycobacterium tuberculosis Strain Related to the KZN Extensively Drug-Resistant M. tuberculosis Strain from South Africa

Multidrug-resistant tuberculosis (MDR-TB) is a significant health problem in Panama. The extent to which such cases are the result of primary or acquired resistance and the strain families involved are unknown. We performed whole-genome sequencing of a collection of 66 clinical MDR isolates, along with 31 drug-susceptible isolates, that were isolated in Panama between 2001 and 2010; 78% of the MDR isolates belong to the Latin American-Mediterranean (LAM) family. Drug resistance mutations correlated well with drug susceptibility profiles. To determine the relationships among these strains and to better understand the acquisition of resistance mutations, a phylogenetic tree was constructed based on a genome-wide single-nucleotide polymorphism analysis. The phylogenetic tree shows that the isolates are highly clustered, with a single strain (LAM9-c1) accounting for nearly one-half of the MDR isolates (29/66 isolates). The LAM9-c1 strain was most prevalent among male patients of working age and was associated with high mortality rates. Members of this cluster all share identical mutations conferring resistance to isoniazid (KatG S315T mutation), rifampin (RpoB S531L mutation), and streptomycin (rrs C517T mutation). This evidence of primary resistance supports a model in which MDR-TB in Panama is driven by clonal expansion and ongoing transmission of several strains in the LAM family, including the highly successful MDR strain LAM9-c1. The phylogenetic analysis also shows that the LAM9-c1 strain is closely related to the KwaZulu-Natal (KZN) extensively drug-resistant TB strain identified in KwaZulu-Natal, South Africa. The LAM9-c1 and KZN strains likely arose from a recent common ancestor that was transmitted between Panama and South Africa and had the capacity to tolerate an accumulation of multiple resistance mutations

Structural basis of fumarate hydratase deficiency

Fumarate hydratase catalyzes the stereospecific hydration across the olefinic double bond in fumarate leading to L-malate. The enzyme is expressed in mitochondrial and cytosolic compartments, and participates in the Krebs cycle in mitochondria, as well as in regulation of cytosolic fumarate levels. Fumarate hydratase deficiency is an autosomal recessive trait presenting as metabolic disorder with severe encephalopathy, seizures and poor neurological outcome. Heterozygous mutations are associated with a predisposition to cutaneous and uterine leiomyomas and to renal cancer. The crystal structure of human fumarate hydratase shows that mutations can be grouped into two distinct classes either affecting structural integrity of the core enzyme architecture, or are localized around the enzyme active site

Structural Similarities and Differences between Two Functionally Distinct SecA Proteins, Mycobacterium tuberculosis SecA1 and SecA2

While SecA is the ATPase component of the major bacterial secretory (Sec) system, mycobacteria and some Gram-positive pathogens have a second paralog, SecA2. In bacteria with two SecA paralogs, each SecA is functionally distinct, and they cannot compensate for one another. Compared to SecA1, SecA2 exports a distinct and smaller set of substrates, some of which have roles in virulence. In the mycobacterial system, some SecA2-dependent substrates lack a signal peptide, while others contain a signal peptide but possess features in the mature protein that necessitate a role for SecA2 in their export. It is unclear how SecA2 functions in protein export, and one open question is whether SecA2 works with the canonical SecYEG channel to export proteins. In this study, we report the structure of Mycobacterium tuberculosis SecA2 (MtbSecA2), which is the first structure of any SecA2 protein. A high level of structural similarity is observed between SecA2 and SecA1. The major structural difference is the absence of the helical wing domain, which is likely to play a role in how MtbSecA2 recognizes its unique substrates. Importantly, structural features critical to the interaction between SecA1 and SecYEG are preserved in SecA2. Furthermore, suppressor mutations of a dominant-negative secA2 mutant map to the surface of SecA2 and help identify functional regions of SecA2 that may promote interactions with SecYEG or the translocating polypeptide substrate. These results support a model in which the mycobacterial SecA2 works with SecYEG. IMPORTANCE SecA2 is a paralog of SecA1, which is the ATPase of the canonical bacterial Sec secretion system. SecA2 has a nonredundant function with SecA1, and SecA2 exports a distinct and smaller set of substrates than SecA1. This work reports the crystal structure of SecA2 of Mycobacterium tuberculosis (the first SecA2 structure reported for any organism). Many of the structural features of SecA1 are conserved in the SecA2 structure, including putative contacts with the SecYEG channel. Several structural differences are also identified that could relate to the unique function and selectivity of SecA2. Suppressor mutations of a secA2 mutant map to the surface of SecA2 and help identify functional regions of SecA2 that may promote interactions with SecYEG